Science.gov

Sample records for agt federal deregulation

  1. School Improvement in the Far West: The Effects of Federal and State Cutbacks, Consolidation, and Deregulation on Education in California, Nevada, and Utah. Final Report.

    ERIC Educational Resources Information Center

    Hood, Paul D.; And Others

    This report explores the effects of federal, state, and local fiscal cutbacks and of federal and state categorical program consolidation and deregulation on the capacity of state, intermediate, and local education agencies to provide instructional improvement services to schools in California, Nevada, and Utah. The planning process and impact of…

  2. AGT100 turbomachinery. [for automobiles

    NASA Technical Reports Server (NTRS)

    Tipton, D. L.; Mckain, T. F.

    1982-01-01

    High-performance turbomachinery components have been designed and tested for the AGT100 automotive engine. The required wide range of operation coupled with the small component size, compact packaging, and low cost of production provide significant aerodynamic challenges. Aerodynamic design and development testing of the centrifugal compressor and two radial turbines are described. The compressor achieved design flow, pressure ratio, and surge margin on the initial build. Variable inlet guide vanes have proven effective in modulating flow capacity and in improving part-speed efficiency. With optimum use of the variable inlet guide vanes, the initial efficiency goals have been demonstrated in the critical idle-to-70% gasifier speed range. The gasifier turbine exceeded initial performance goals and demonstrated good performance over a wide range. The radial power turbine achieved 'developed' efficiency goals on the first build.

  3. AGT (Advanced Gas Turbine) technology project

    NASA Technical Reports Server (NTRS)

    1988-01-01

    An overall summary documentation is provided for the Advanced Gas Turbine Technology Project conducted by the Allison Gas Turbine Division of General Motors. This advanced, high risk work was initiated in October 1979 under charter from the U.S. Congress to promote an engine for transportation that would provide an alternate to reciprocating spark ignition (SI) engines for the U.S. automotive industry and simultaneously establish the feasibility of advanced ceramic materials for hot section components to be used in an automotive gas turbine. As this program evolved, dictates of available funding, Government charter, and technical developments caused program emphases to focus on the development and demonstration of the ceramic turbine hot section and away from the development of engine and powertrain technologies and subsequent vehicular demonstrations. Program technical performance concluded in June 1987. The AGT 100 program successfully achieved project objectives with significant technology advances. Specific AGT 100 program achievements are: (1) Ceramic component feasibility for use in gas turbine engines has been demonstrated; (2) A new, 100 hp engine was designed, fabricated, and tested for 572 hour at operating temperatures to 2200 F, uncooled; (3) Statistical design methodology has been applied and correlated to experimental data acquired from over 5500 hour of rig and engine testing; (4) Ceramic component processing capability has progressed from a rudimentary level able to fabricate simple parts to a sophisticated level able to provide complex geometries such as rotors and scrolls; (5) Required improvements for monolithic and composite ceramic gas turbine components to meet automotive reliability, performance, and cost goals have been identified; (6) The combustor design demonstrated lower emissions than 1986 Federal Standards on methanol, JP-5, and diesel fuel. Thus, the potential for meeting emission standards and multifuel capability has been initiated

  4. Advanced Gas Turbine (AGT) powertrain system development for automotive applications

    NASA Technical Reports Server (NTRS)

    1982-01-01

    A gas turbine powertrain for automobiles with reduced fuel consumption and reduced environmental impact is investigated. The automotive gas turbine, when installed in an automobile (3000 pounds inertia weight), provides a CFDC fuel economy of 42.8 miles per gallon based on EPA test procedures and diesel No. 2 fuel. The AGT powered vehicle substantially gives the same overall vehicle driveability and performance as a comparable production vehicle powered by a conventional spark ignition powertrain system. The emissions are less than federal standards, and a variety of fuels can be used.

  5. Advanced Gas Turbine (AGT) technology development project

    NASA Technical Reports Server (NTRS)

    1987-01-01

    This report is the final in a series of Technical Summary Reports for the Advanced Gas Turbine (AGT) Technology Development Project, authorizrd under NASA Contract DEN3-167 and sponsored by the DOE. The project was administered by NASA-Lewis Research Center of Cleveland, Ohio. Plans and progress are summarized for the period October 1979 through June 1987. This program aims to provide the US automotive industry the high risk, long range technology necessary to produce gas turbine engines for automobiles that will reduce fuel consumption and reduce environmental impact. The intent is that this technology will reach the marketplace by the 1990s. The Garrett/Ford automotive AGT was designated AGT101. The AGT101 is a 74.5 kW (100 shp) engine, capable of speeds to 100,000 rpm, and operates at turbine inlet temperatures to 1370 C (2500 F) with a specific fuel consumption level of 0.18 kg/kW-hr (0.3 lbs/hp-hr) over most of the operating range. This final report summarizes the powertrain design, power section development and component/ceramic technology development.

  6. Confronting Deregulation.

    ERIC Educational Resources Information Center

    Madget, James

    1997-01-01

    Discusses how schools can capitalize on new opportunities for cost savings and improved service in a deregulated electric industry. It discusses strategies for preparing to buy electrical power on the open market and examines two forms of purchasing called "wholesale-wheeling" and "retail-wheeling." Steps in conducting a utility audit are…

  7. Selberg integral and SU( N) AGT conjecture

    NASA Astrophysics Data System (ADS)

    Zhang, Hong; Matsuo, Yutaka

    2011-12-01

    An intriguing coincidence between the partition function of super Yang-Mills theory and correlation functions of 2d Toda system has been heavily studied recently. While the partition function of gauge theory was explored by Nekrasov, the correlation functions of Toda equation have not been completely understood. In this paper, we study the latter in the form of Dotsenko-Fateev integral and reduce it in the form of Selberg integral of several Jack polynomials. We conjecture a formula for such Selberg average which satisfies some consistency conditions and show that it reproduces the SU( N) version of AGT conjecture.

  8. Advanced Gas Turbine (AGT) powertrain system development for automotive applications

    NASA Technical Reports Server (NTRS)

    1982-01-01

    Topics covered include the AGT 101 engine test; compressor design modification; cold air turbine testing; Mod 1 alloy turbine rotor fabrication; combustion aspects; regenerator development; and thermal screening tests for ceramic materials. The foil gas bearings, rotor dynamics, and AGT controls and accessories are also considered.

  9. An Interrupted Time-Series Analysis of Durkheim's Social Deregulation Thesis: The Case of the Russian Federation.

    PubMed

    Pridemore, William Alex; Chamlin, Mitchell B; Cochran, John K

    2007-06-01

    The dissolution of the Soviet Union resulted in sudden, widespread, and fundamental changes to Russian society. The former social welfare system-with its broad guarantees of employment, healthcare, education, and other forms of social support-was dismantled in the shift toward democracy, rule of law, and a free-market economy. This unique natural experiment provides a rare opportunity to examine the potentially disintegrative effects of rapid social change on deviance, and thus to evaluate one of Durkheim's core tenets. We took advantage of this opportunity by performing interrupted time-series analyses of annual age-adjusted homicide, suicide, and alcohol-related mortality rates for the Russian Federation using data from 1956 to 2002, with 1992-2002 as the postintervention time-frame. The ARIMA models indicate that, controlling for the long-term processes that generated these three time series, the breakup of the Soviet Union was associated with an appreciable increase in each of the cause-of-death rates. We interpret these findings as being consistent with the Durkheimian hypothesis that rapid social change disrupts social order, thereby increasing the level of crime and deviance.

  10. Advanced Gas Turbine (AGT) technology report

    NASA Technical Reports Server (NTRS)

    1985-01-01

    Engine testing, ceramic component fabrication and evaluation, component performance rig testing, and producibility experiments at Pontiac comprised AGT 100 activities of this period, January to December 1984. Two experimental engines were available and allowed the evaluation of eight experimental assemblies. Operating time accumulated was 115 hr of burning and 156 hr total. Total cumulative engine operating time is now 225 hr. Build number 11 and 12 of engine S/N 1 totaled 28 burning hours and constituted a single assembly of the engine core--the compressor, both turbines, and the gearbox. Build number 11 of engine S/N 1 included a 1:07 hr continuous test at 100% gasifier speed (86,000 rpm). Build number 8 of engine S/N 2 was the first engine test with a ceramic turbine rotor. A mechanical loss test of an engine assembly revealed the actual losses to be near the original design allowance. Component development activity included rig testing of the compressor, combustor, and regenerator. Compressor testing was initiated on a rig modified to control the transfer of heat between flow path, lubricating oil, and structure. Results show successful thermal decoupling of the rig and lubricating/cooling oil. Rig evaluation of a reduced-friction compressor was initiated. Combustor testing covered qualification of ceramic parts for engine use, mapping of operating range limits, and evaluation of a relocated igniter plug. Several seal refinements were tested on the hot regenerator rig. An alternate regenerator disk, extruded MAS, was examined and found to be currently inadequate for the AGT 100 application. Also, a new technique for measuring leakage was explored on the regenerator rig. Ceramic component activity has focused on the development of state-of-the-art material strength characteristics in full-scale hardware. Injection-molded sintered alpha-SiC rotors were produced at Carborundum in an extensive process and tool optimization study.

  11. Advanced Gas Turbine (AGT) Technology Project

    NASA Technical Reports Server (NTRS)

    1986-01-01

    Engine testing, ceramic component fabrication and evaluation, component performance rig testing, and analytical studies comprised AGT 100 activities during the 1985 year. Ten experimental assemblies (builds) were evaluated using two engines. Accrued operating time was 120 hr of burning and 170 hr total, bringing cumulative total operating time to 395 hr, all devoid of major failures. Tests identified the generator seals as the primary working fluid leakage sources. Power transfer clutch operation was demonstrated. An alpha SiC gasifier rotor engine test resulted in blade tip failures. Recurring case vibration and shaft whip have limited gasifier shaft speeds to 84%. Ceramic components successfully engine tested now include the SiC scroll assembly, Si3N3 turbine rotor, combustor assembly, regenerator disk bulkhead, turbine vanes, piston rings, and couplings. A compressor shroud design change to reduce heat recirculation back to the inlet was executed. Ceramic components activity continues to focus on the development of state-of-the-art material strength characteristics in full-scale engine hardware. Fiber reinforced glass-ceramic composite turbine (inner) backplates were fabricated by Corning Glass Works. The BMAS/III material performed well in engine testing. Backplates of MAS material have not been engine tested.

  12. Advanced Gas Turbine (AGT) Technology Development Project

    NASA Technical Reports Server (NTRS)

    1987-01-01

    This report is the eleventh in the series of Technical Summary reports for the Advanced Gas Turbine (AGT) Technology Development Project, authorized under NASA Contract DEN3-167, and sponsored by the Department of Energy (DOE). This report was prepared by Garrett Turbine Engine Company, A Division of the Garrett Corporation, and includes information provided by Ford Motor Company, the Standard Oil Company, and AiResearch Casting Company. This report covers plans and progress for the period July 1, 1985 through June 30, 1986. Technical progress during the reported period was highlighted by the 85-hour endurance run of an all-ceramic engine operating in the 2000 to 2250 F temperature regime. Component development continued in the areas of the combustion/fuel injection system, regenerator and seals system, and ceramic turbine rotor attachment design. Component rig testing saw further refinements. Ceramic materials showed continued improvements in required properties for gas turbine applications; however, continued development is needed before performance and reliability goals can be set.

  13. Advanced Gas Turbine (AGT) Technology Development Project, ceramic component developments

    NASA Technical Reports Server (NTRS)

    Teneyck, M. O.; Macbeth, J. W.; Sweeting, T. B.

    1987-01-01

    The ceramic component technology development activity conducted by Standard Oil Engineered Materials Company while performing as a principal subcontractor to the Garrett Auxiliary Power Division for the Advanced Gas Turbine (AGT) Technology Development Project (NASA Contract DEN3-167) is summarized. The report covers the period October 1979 through July 1987, and includes information concerning ceramic technology work categorized as common and unique. The former pertains to ceramic development applicable to two parallel AGT projects established by NASA contracts DEN3-168 (AGT100) and DEN3-167 (AGT101), whereas the unique work solely pertains to Garrett directed activity under the latter contract. The AGT101 Technology Development Project is sponsored by DOE and administered by NASA-Lewis. Standard Oil directed its efforts toward the development of ceramic materials in the silicon-carbide family. Various shape forming and fabrication methods, and nondestructive evaluation techniques were explored to produce the static structural components for the ceramic engine. This permitted engine testing to proceed without program slippage.

  14. Deregulation of electric utilities

    SciTech Connect

    Zaccour, G.

    1998-07-01

    This volume is a collection of fourteen, mainly applied, economic papers examining electric utility deregulation in many parts of the world. These papers were presented at the International Workshop on Deregulation of Electric Utilities held in Montreal, Canada in September 1997. As the title suggests, these papers cover a broad range of topics. Despite the book's scattershot approach, a small subset of contributors asks a fundamental question: Is the industry sufficiently deregulated? This book succeeds in providing some concrete and well-analyzed examples that examine this important question.

  15. Field testing advanced geothermal turbodrill (AGT). Phase 1 final report

    SciTech Connect

    Maurer, W.C.; Cohen, J.H.

    1999-06-01

    Maurer Engineering developed special high-temperature geothermal turbodrills for LANL in the 1970s to overcome motor temperature limitations. These turbodrills were used to drill the directional portions of LANL`s Hot Dry Rock Geothermal Wells at Fenton Hill, New Mexico. The Hot Dry Rock concept is to drill parallel inclined wells (35-degree inclination), hydraulically fracture between these wells, and then circulate cold water down one well and through the fractures and produce hot water out of the second well. At the time LANL drilled the Fenton Hill wells, the LANL turbodrill was the only motor in the world that would drill at the high temperatures encountered in these wells. It was difficult to operate the turbodrills continuously at low speed due to the low torque output of the LANL turbodrills. The turbodrills would stall frequently and could only be restarted by lifting the bit off bottom. This allowed the bit to rotate at very high speeds, and as a result, there was excessive wear in the bearings and on the gauge of insert roller bits due to these high rotary speeds. In 1998, Maurer Engineering developed an Advanced Geothermal Turbodrill (AGT) for the National Advanced Drilling and Excavation Technology (NADET) at MIT by adding a planetary speed reducer to the LANL turbodrill to increase its torque and reduce its rotary speed. Drilling tests were conducted with the AGT using 12 1/2-inch insert roller bits in Texas Pink Granite. The drilling tests were very successful, with the AGT drilling 94 ft/hr in Texas Pink Granite compared to 45 ft/hr with the LANL turbodrill and 42 ft/hr with a rotary drill. Field tests are currently being planned in Mexico and in geothermal wells in California to demonstrate the ability of the AGT to increase drilling rates and reduce drilling costs.

  16. Advanced Gas Turbine (AGT) Technology Development Project annual report

    NASA Technical Reports Server (NTRS)

    1986-01-01

    This report is the tenth in a series of Technical Summary reports for the Advanced Gas Turbine (AGT) Technology Development Project, authorized under NASA Contract DEN3-167, and sponsored by the Department of Energy (DOE). This report was prepared by Garrett Turbine Engine Company, A Division of the Garrett Corporation, and includes information provided by Ford Motor Company, the Carborundum Company, and AiResearch Casting Company. The Project is administered by Mr. Thomas N. Strom, Project Manager, NASA-Lewis Research Center, Cleveland, Ohio. This report covers plans and progress for the period July 1, 1984 through June 30, 1985.

  17. AGT relations for abelian quiver gauge theories on ALE spaces

    NASA Astrophysics Data System (ADS)

    Pedrini, Mattia; Sala, Francesco; Szabo, Richard J.

    2016-05-01

    We construct level one dominant representations of the affine Kac-Moody algebra gl̂k on the equivariant cohomology groups of moduli spaces of rank one framed sheaves on the orbifold compactification of the minimal resolution Xk of the Ak-1 toric singularity C2 /Zk. We show that the direct sum of the fundamental classes of these moduli spaces is a Whittaker vector for gl̂k, which proves the AGT correspondence for pure N = 2 U(1) gauge theory on Xk. We consider Carlsson-Okounkov type Ext-bundles over products of the moduli spaces and use their Euler classes to define vertex operators. Under the decomposition gl̂k ≃ h ⊕sl̂k, these vertex operators decompose as products of bosonic exponentials associated to the Heisenberg algebra h and primary fields of sl̂k. We use these operators to prove the AGT correspondence for N = 2 superconformal abelian quiver gauge theories on Xk.

  18. Advanced Gas Turbine (AGT) powertrain system development for automotive applications

    NASA Technical Reports Server (NTRS)

    1980-01-01

    Progress in the development of a gas turbine engine to improve fuel economy, reduce gaseous emissions and particulate levels, and compatible with a variety of alternate fuels is reported. The powertrain is designated AGT101 and consists of a regenerated single shaft gas turbine engine, a split differential gearbox and a Ford Automatic Overdrive production transmission. The powertrain is controlled by an electronic digital microprocessor and associated actuators, instrumentation, and sensors. Standard automotive accessories are driven by engine power provided by an accessory pad on the gearbox. Component/subsystem development progress is reported in the following areas: compressor, turbine, combustion system, regenerator, gearbox/transmission, structures, ceramic components, foil gas bearing, bearings and seals, rotor dynamics, and controls and accessories.

  19. Advanced Gas Turbine (AGT) powertrain system development for automotive applications

    NASA Technical Reports Server (NTRS)

    1981-01-01

    An automotive gas turbine powertrain system which, when installed in a 1985 production vehicle (3000 pounds inertia weight), is being developed with a CFDC fuel economy of 42.8 miles per gallon based on Environmental Protection Agency (EPA) test procedures and diesel No. 2 fuel. The AGT-powered vehicle shall give substantially the same overall vehicle driveability and performance as a comparable 1985 production vehicle powered by a conventional spark ignition powertrain system (baseline system). Gaseous emissions and particulate levels less than: NOx = 0.4 gm/mile, HC = 0.41 gm/mile, and CO = 3.4 gm/mile, and a total particulate of 0.2 gm/mile, using the same fuel as used for fuel economy measurements is expected, along with the ability to use a variety of alternate fuels.

  20. National policy in a deregulated marketplace

    SciTech Connect

    Jensen, V.

    1996-12-31

    This paper is one of three keynote presentations given at the conference. It briefly discusses government policy issues regarding electric utility deregulation. Three major questions are examined: (1) policies and institutions required to ensure a free market, (2) allocation of stranded assets and ensuring that consumers benefit from restructuring, and (3) continuation of collateral utility activities such as low income program investments, energy efficiency, and renewable energy use. Types of policy options under consideration are reviewed, and potential state and federal roles are described.

  1. Biomass in the Deregulated Marketplace: Current Issues for Biomass Power

    SciTech Connect

    Not Available

    1998-12-01

    This issue brief provides readers with a monthly review and analysis of electric utility deregulation as it impacts biomass power production and distribution. The topical areas to be routinely covered will include Federal activities, State activities, Current challenges, and Current opportunities. Additionally, a monthly highlighted topic will provide more in-depth analysis of current issue impacting biomass power.

  2. The Impact of Television Deregulation on Private and Public Interests.

    ERIC Educational Resources Information Center

    Ferrall, Victor E., Jr.

    1989-01-01

    Examines the impact of six years (1981-1987) of television deregulation by the United States Federal Communications Commission (FCC). Contends that the FCC's rule deletions have altered economic relations among segments of the television industry and its users, and discusses effects on the future of "free" television. (MS)

  3. Towards the Proof of AGT Relations with the Help of the Generalized Jack Polynomials

    NASA Astrophysics Data System (ADS)

    Morozov, Alexei; Smirnov, Andrey

    2014-05-01

    Original proofs of the AGT relations with the help of the Hubbard-Stratanovich duality of the modified Dotsenko-Fateev matrix model did not work for β ≠ 1, because Nekrasov functions were not properly reproduced by Selberg-Kadell integrals of Jack polynomials. We demonstrate that if the generalized Jack polynomials, depending on the N-ples of Young diagrams from the very beginning, are used instead of the N-linear combinations of ordinary Jacks, this resolves the problem. Such polynomials naturally arise as special elements in the equivariant cohomologies of the GL( N)-instanton moduli spaces, and this also establishes connection to alternative ABBFLT approach to the AGT relations, studying the action of chiral algebras on the instanton moduli spaces. In this paper, we describe a complete proof of AGT in the simple case of GL(2) ( N = 2) Yang-Mills theory, i.e., the 4-point spherical conformal block of the Virasoro algebra.

  4. Resolving the contributions of two cooperative mechanisms to the DNA binding of AGT.

    PubMed

    Melikishvili, Manana; Fried, Michael G

    2015-09-01

    The O(6)-alkylguanine DNA alkyltransferase (AGT) is a DNA repair enzyme that binds DNA with moderate cooperativity. This cooperativity is important for its search for alkylated bases. A structural model of the cooperative complex of AGT with DNA predicts short-range interactions between nearest protein neighbors and long-range interactions between proteins separated in the array. DNA substrates ranging from 11bp to 30bp allowed us to use differences in binding stoichiometry to resolve short- and long-range protein contributions to the stability of AGT complexes. We found that the short-range component of ΔG°(coop) was nearly independent of DNA length and protein packing density. In contrast the long-range component oscillated with DNA length, with a period equal to the occluded binding site size (4bp). The amplitude of the long-range component decayed from ∼-4 kcal/mole of interaction to ∼-1.2 kcal/mol of interaction as the size of cooperative unit increased from 4 to 7 proteins, suggesting a mechanism to limit the size of cooperative clusters. These features allow us to make testable predictions about AGT distributions and interactions with chromatin structures in vivo. PMID:26017689

  5. Resolving the contributions of two cooperative mechanisms to the DNA Binding of AGT

    PubMed Central

    Melikishvili, Manana

    2015-01-01

    ABSTRACT The O6‐alkylguanine DNA alkyltransferase (AGT) is a DNA repair enzyme that binds DNA with moderate cooperativity. This cooperativity is important for its search for alkylated bases. A structural model of the cooperative complex of AGT with DNA predicts short‐range interactions between nearest protein neighbors and long‐range interactions between proteins separated in the array. DNA substrates ranging from 11bp to 30bp allowed us to use differences in binding stoichiometry to resolve short‐ and long‐range protein contributions to the stability of AGT complexes. We found that the short‐range component of ΔG°coop was nearly independent of DNA length and protein packing density. In contrast the long‐range component oscillated with DNA length, with a period equal to the occluded binding site size (4bp). The amplitude of the long‐range component decayed from ∼−4 kcal/mole of interaction to ∼−1.2 kcal/mol of interaction as the size of cooperative unit increased from 4 to 7 proteins, suggesting a mechanism to limit the size of cooperative clusters. These features allow us to make testable predictions about AGT distributions and interactions with chromatin structures in vivo. © 2015 The Authors Biopolymers Published by Wiley Periodicals, Inc. Biopolymers 103: 509–516, 2015. PMID:26017689

  6. Inconsistency Across Time and Situations: A Decade of Research Using the Adjective Generation Technique (AGT).

    ERIC Educational Resources Information Center

    Allen, Bem P.; Potkay, Charles R.

    The Adjective Generation Technique (AGT) has been used in studies to demonstrate that subjects' responses show variations from one point in time to the next. To examine this hypothesis, longitudinal studies were undertaken where subjects were asked to generate five words to describe themselves on each of 29 days. Some conclusions drawn were that:…

  7. Identification of regulatory elements in the AGT1 promoter of ale and lager strains of brewer's yeast.

    PubMed

    Vidgren, Virve; Kankainen, Matti; Londesborough, John; Ruohonen, Laura

    2011-08-01

    Agt1 is an interesting α-glucoside transporter for the brewing industry, as it efficiently transports maltotriose, a sugar often remaining partly unused during beer fermentation. It has been shown that on maltose the expression level of AGT1 is much higher in ale strains than in lager strains, and that glucose represses the expression, particularly in the ale strains. In the present study the regulatory elements of the AGT1 promoter of one ale and two lager strains were identified by computational methods. Promoter regions up to 1.9 kbp upstream of the AGT1 gene were sequenced from the three brewer's yeast strains and the laboratory yeast strain CEN.PK-1D. The promoter sequence of the laboratory strain was identical to the AGT1 promoter of strain S288c of the Saccharomyces Genome Database, whereas the promoter sequences of the industrial strains diverged markedly from the S288c strain. The AGT1 promoter regions of the ale and lager strains were for the most part identical to each other, except for one 22 bp deletion and two 94 and 95 bp insertions in the ale strain. Computational analyses of promoter elements revealed that the promoter sequences contained several Mig1- and MAL-activator binding sites, as was expected. However, some of the Mig1 and MAL-activator binding sites were located on the two insertions of the ale strain, and thus offered a plausible explanation for the different expression pattern of the AGT1 gene in the ale strains. Accordingly, functional analysis of A60 ale and A15 lager strain AGT1 promoters fused to GFP (encoding the green fluorescent protein) showed a significant difference in the ability of these two promoters to drive GFP expression. Under the control of the AGT1 promoter of the ale strain the emergence of GFP was strongly induced by maltose, whereas only a low level of GFP was detected with the construct carrying the AGT1 promoter of the lager strain. Thus, the extra MAL-activator binding element, present in the AGT1 promoter of

  8. Angiotensinogen (AGT) M235T, AGT T174M and Angiotensin-1-Converting Enzyme (ACE) I/D Gene Polymorphisms in Essential Hypertension: Effects on Ramipril Efficacy

    PubMed Central

    Kolovou, Vana; Lagou, Evangelia; Mihas, Constantinos; Vasiliki, Giannakopoulou; Katsiki, Niki; Kollia, Aikaterini; Triposkiadis, Filippos; Degiannis, Dimitris; Mavrogeni, Sophie; Kolovou, Genovefa

    2015-01-01

    Background: Hypertension, one of the most important risk factors for premature cardiovascular disease, is a major worldwide public health problem. Angiotensin-1-converting enzyme (ACE) and angiotensinogen (AGT) gene polymorphisms are thought to be associated with primary hypertension. In the present study, we examined the frequency of these gene polymorphisms in an adult population with and without essential hypertension. Furthermore, we evaluated the effect of ACE and AGT gene polymorphisms on ramipril treatment efficacy in the hypertensive patients. Methods: A total of 166 adults (83 hypertensives and 83 normotensives) were involved in the study and genotyped for AGTM235T (rs699), AGTT174M (rs4762) and ACEI/D (rs1799752) gene polymorphisms. Results: The genotype and allele distribution of the AGTM235T variant significantly differed between hypertensives and normotensives [odds ratio (OR) = 1.57% (T vs M allele), 95% confidence intervals (CIs): 1.01 - 2.44; p=0.045 for hypertensives]. However, none of the 3 studied Simple Nucleotide Polymorphisms were associated with the blood pressure-lowering response to ramipril. Conclusion: These results suggest that AGTM235T gene polymorphism is associated with essential hypertension. However, none of the AGTM235T, AGTT174M and ACEI/D gene polymorphisms influenced ramipril effectiveness. PMID:27006715

  9. MET deregulation in breast cancer

    PubMed Central

    Landi, Lorenza

    2015-01-01

    Background Mesenchymal-epithelial transition (MET) is an oncogene encoding for a trans-membrane tyrosine kinase receptor activated by the hepatocyte growth factor (HGF). MET has a normal function in organ development during embryogenesis and in tissue homeostasis during adult life. Deregulation of HGF/MET signaling pathway is frequently observed in many cancer types, conferring invasive growth and tendency to progression. MET deregulation is due to gene amplification or increased copy number, gene mutation, receptor over-expression or ligand autocrine loops activation. These events lead to migration, invasion, proliferation, metastatic spread and neo-angiogenesis of cancer cells, suggesting that anti-HGF/MET agents may represent a potential antitumor strategy. In breast cancer (BC), preclinical and clinical data demonstrated the role of HGF/MET signalling pathway in carcinogenesis, disease progression and resistance features. Methods For this review article, all published data on HGF/MET in BC were collected and analyzed. Results Several evidences underline that, in early BC, MET over-expression has an independent negative prognostic significance, regardless of method used for evaluation and BC subtypes. Available data suggest that MET is a relevant target particularly in basal-like (BL) and in triple negative BC. Moreover, preclinical and retrospective data support the critical role of MET deregulation in the development of resistance to target-agents, such as anti-HER2 strategies. Conclusions MET is a promising new target in BC. Several anti-MET agents are under investigation and ongoing clinical trials will clarify its relevance in BC treatment. PMID:26366398

  10. Three Agt1 transporters from brewer's yeasts exhibit different temperature dependencies for maltose transport over the range of brewery temperatures (0–20 °C).

    PubMed

    Vidgren, Virve; Viljanen, Kaarina; Mattinen, Laura; Rautio, Jari; Londesborough, John

    2014-06-01

    Zero-trans rates of maltose transport by brewer's yeasts exert strong control over fermentation rates and are strongly temperature-dependent over the temperature range (20–0 °C) of brewery fermentations. Three α-glucoside transporters, ScAgt1(A60) (a Saccharomyces cerevisiae version of Agt1 from an ale strain), ScAgt1-A548V (a variant of ScAgt1(A60) with a single amino acid change in a transmembrane domain), and SbAgt1 (a Saccharomyces (eu)bayanus version from a lager strain), were compared. When expressed in the same laboratory yeast, grown at 24 °C and assayed at 0, 10, and 20 °C, SbAgt1 had the lowest absolute maltose uptake activity at 20 °C but smallest temperature dependence, ScAgt1-A548V had the highest activity but greatest temperature dependence, and ScAgt1(A60) had intermediate properties. ScAgt1(A60) exhibited higher absolute rates and smaller temperature dependencies when expressed in laboratory rather than brewer's strains. Absolute rates closely reflected the amounts of GFP-tagged ScAgt1(A60) transporter in each host's plasma membrane. Growth at 15 °C instead of 24 °C decreased the absolute activities of strains expressing ScAgt1(A60) by two- to threefold. Evidently, the kinetic characteristics of at least ScAgt1(A60) depended on the nature of the host plasma membrane. However, no consistent correlation was observed between transport activities and fatty acid or ergosterol compositions. PMID:25035870

  11. Advanced Gas Turbine (AGT) powertrain system initial development report

    NASA Technical Reports Server (NTRS)

    1980-01-01

    The powertrain consists of a single shaft regenerated gas turbine engine utilizing ceramic hot section components, coupled to a slit differential gearbox with an available variable stator torque converter and an available Ford intergral overdrive four-speed automatic transmission. Predicted fuel economy using gasoline fuel over the combined federal driving cycle (CFDC) is 15.3 km/1, which represents a 59% improvement over the spark-ignition-powered baseline vehicle. Using DF2 fuel, CFDC mileage estimates are 17.43 km/1. Zero to 96.6 km/hr acceleration time is 11.9 seconds with a four-second accleration distance of 21.0 m. The ceramic radial turbine rotor is discussed along with the control system for the powertrain.

  12. A polymorphism in AGT and AGTR1 gene is associated with lead-related high blood pressure.

    PubMed

    Kim, Hyung-Ki; Lee, Hwayoung; Kwon, Jun-Tack; Kim, Hak-Jae

    2015-12-01

    We investigated the association of polymorphisms in two renin-angiotensin system-related genes, expressed as angiotensinogen (AGT) and angiotensin II type 1 receptor (AGTR1), with blood lead levels and lead-related blood pressure in lead-exposed male workers in Korea. A cross-sectional study involving 808 lead-exposed male workers in Korea was conducted using a restriction fragment length polymorphism-based strategy to differentiate the various genotypes of polymorphisms in the AGT and AGTR1 genes. The association of clinical characteristics with genotypes as modifiers was estimated after adjustment for age, smoking status, drinking status, body mass index and job duration of each subject. Genotype and allele frequencies of the M235T polymorphism in AGT were associated with lead-related high blood pressure status. Moreover, blood lead levels were associated with allele frequencies of the AGT M235T polymorphism. These results suggested that the M/M genotype and M allele of AGT are risk factors for lead-related high blood pressure.

  13. Improved Fermentation Performance of a Lager Yeast after Repair of Its AGT1 Maltose and Maltotriose Transporter Genes▿ †

    PubMed Central

    Vidgren, Virve; Huuskonen, Anne; Virtanen, Hannele; Ruohonen, Laura; Londesborough, John

    2009-01-01

    The use of more concentrated, so-called high-gravity and very-high-gravity (VHG) brewer's worts for the manufacture of beer has economic and environmental advantages. However, many current strains of brewer's yeasts ferment VHG worts slowly and incompletely, leaving undesirably large amounts of maltose and especially maltotriose in the final beers. α-Glucosides are transported into Saccharomyces yeasts by several transporters, including Agt1, which is a good carrier of both maltose and maltotriose. The AGT1 genes of brewer's ale yeast strains encode functional transporters, but the AGT1 genes of the lager strains studied contain a premature stop codon and do not encode functional transporters. In the present work, one or more copies of the AGT1 gene of a lager strain were repaired with DNA sequence from an ale strain and put under the control of a constitutive promoter. Compared to the untransformed strain, the transformants with repaired AGT1 had higher maltose transport activity, especially after growth on glucose (which represses endogenous α-glucoside transporter genes) and higher ratios of maltotriose transport activity to maltose transport activity. They fermented VHG (24° Plato) wort faster and more completely, producing beers containing more ethanol and less residual maltose and maltotriose. The growth and sedimentation behaviors of the transformants were similar to those of the untransformed strain, as were the profiles of yeast-derived volatile aroma compounds in the beers. PMID:19181838

  14. Deregulation: Implications for Community College Leaders.

    ERIC Educational Resources Information Center

    Bender, Louis W.

    1986-01-01

    Looks at the ways in which the deregulation of business and industry may affect community colleges in the years ahead, using the banking industry as an illustration. Argues that the deregulation of higher education requires that community college leadership programs examine past assumptions and develop new strategies. (LAL)

  15. Power Buying: Planning For Your Deregulated Future.

    ERIC Educational Resources Information Center

    Robertson, Wayne K.

    1997-01-01

    Colleges and universities can benefit from the coming deregulation of utilities. Deregulation creates opportunity for facility managers to aggressively negotiate agreements, implement changes to the physical plant to make the institution a more attractive customer, and explore new, less expensive energy supply options and alternatives. Some action…

  16. Deregulation: increased competition is making airlines more efficient and responsive to consumers

    SciTech Connect

    Not Available

    1985-11-06

    The Airline Deregulation Act of 1978 gave domestic airlines, after 40 years of regulation, the freedom to decide where they would fly and what fares they would charge. GAO's review of airline operations before and after deregulation through 1984 shows that most passengers benefited as the industry became more competitive: fare increases were lower, on average, than what might have been expected under continued regulation; the numbers of flights and available seats increased; airlines have been more responsive to consumer preferences through a wider range of price/service options; and operating efficiency has increased. Increasing airport congestion may bring federal action to restrict airline access - action that could offset some of deregulation's benefits. While some favorable trends in fares and services have emerged, further changes are likely as airlines continue to adapt to deregulation.

  17. Oligodeoxynucleotides as substrates for O/sup 6/-alkylguanine-DNA alkyltransferase (AGT)

    SciTech Connect

    Scicchitano, D.; Jones, R.A.; Kuzmich, S.; Gaffney, B.; Lasko, D.; Essigmann, J.; Pegg, A.E.

    1986-05-01

    AGT is a DNA repair protein which is known to catalyze the transfer of alkyl groups from the O/sup 6/-position of guanine in alkylated DNA to a cysteine acceptor site contained within its own protein sequence. The authors have examined the ability of this protein isolated from both E. coli and mammalian cells to carry out this reaction using oligodeoxynucleotides containing O/sup 6/-methylguanine (m/sup 6/G). Dodecadeoxynucleotides of the sequence 5'-dCGBGAATTCm/sup 6/GCG-3' where B is any one of the normal 4 bases were all repaired very rapidly with 50% repair in less than 15 sec at 0/sup 0/C. The hexadeoxynucleotide 5'-dCGCm/sup 6/GCG-3' was repaired slightly more slowly with 50% removal requiring 7 min at 0/sup 0/C and 1.5 min at 37/sup 0/C. The tetradeoxynucleotide 5'-dTm/sup 6/GCA-3' was also a substrate for the protein but was repaired much more slowly requiring 45 min for 50% repair at 37/sup 0/C. These results indicate that (a) the AGT has a strong but not absolute preference for double stranded DNA substrates; (b) the repair of m/sup 6/G is independent of the base opposite the lesion; and (c) that very short oligodeoxynucleotides are substrates for repair by this protein. The latter property was used to set up a very sensitive assay procedure for the AGT. The 5' end of the 5'-dTm/sup 6/GCA-3' was labeled with /sup 32/P by use of polynucleotide kinase and the formation of (/sup 32/P)-5'-dTGACA-3' monitored by separating the methylated form from the unmethylated form by HPLC.

  18. Advanced Gas Turbine (AGT) powertrain system development for automotive applications report

    NASA Technical Reports Server (NTRS)

    1984-01-01

    This report describes progress and work performed during January through June 1984 to develop technology for an Advanced Gas Turbine (AGT) engine for automotive applications. Work performed during the first eight periods initiated design and analysis, ceramic development, component testing, and test bed evaluation. Project effort conducted under this contract is part of the DOE Gas Turbine Highway Vehicle System Program. This program is oriented at providing the United States automotive industry the high-risk long-range techology necessary to produce gas turbine engines for automobiles with reduced fuel consumption and reduced environmental impact. Technology resulting from this program is intended to reach the marketplace by the early 1990s.

  19. Public health sector unions and deregulation in Europe.

    PubMed

    Lethbridge, Jane

    2004-01-01

    Deregulation and liberalization of health services take several forms in Europe: public-private partnerships; contracting out of services; and corporatization of health care institutions. The impact on health workers includes changes in terms and conditions of employment, breakup of collective bargaining agreements, and often more stressful working conditions. The author examines four types of trade union responses to deregulation. National health trade union action has used campaigning, awareness raising, and judicial review. Health workers' unions in alliance with other trade unions have taken part in wider campaigns against privatization and in promoting public services. Health workers' unions joining with social movements have become involved in wider alliances that link with broader public policy issues such as poverty reduction and urban/regional regeneration. European-wide action, seen through the work of the European Federation of Public Service Unions, has concentrated on the development of an alternative health policy, and the promotion of social dialogue at a European level. Trade unions must adopt a range of approaches to challenge the effects of deregulation. Increasingly, trade union members need to be aware of how to take action at both the national and European levels. PMID:15346679

  20. Role of ACE and AGT gene polymorphisms in genetic susceptibility to diabetes mellitus type 2 in a Brazilian sample.

    PubMed

    Wollinger, L M; Dal Bosco, S M; Rempe, C; Almeida, S E M; Berlese, D B; Castoldi, R P; Arndt, M E; Contini, V; Genro, J P

    2015-12-29

    The aim of the current study was to investigate the association between the InDel polymorphism in the angiotensin I-converting enzyme gene (ACE) and the rs699 polymorphism in the angiotensinogen gene (AGT) and diabetes mellitus type 2 (DM2) in a sample population from Southern Brazil. A case-control study was conducted with 228 patients with DM2 and 183 controls without DM2. The ACE InDel polymorphism was genotyped by polymerase chain reaction (PCR) with specific primers, followed by electrophoresis on 1.5% agarose gel. The AGT rs699 polymorphism was genotyped using a real-time PCR assay. No significant association between the ACE InDel polymorphism and DM2 was detected (P = 0.97). However, regarding the AGT rs699 polymorphism, DM2 patients had a significantly higher frequency of the AG genotype and lower frequency of the GG genotype when compared to the controls (P = 0.03). Our results suggest that there is an association between the AGT rs699 polymorphism and DM2 in a Brazilian sample.

  1. Beyond Deregulation: Communications Policy and Economic Growth.

    ERIC Educational Resources Information Center

    Chisman, Forrest P.

    1982-01-01

    Despite deregulation, major barriers to the growth of U.S. information industries are not being addressed or are being addressed badly. As a result, the full potential of one of our highest productivity industries and its contribution to national productivity are not being realized. (PD)

  2. Deregulation-restructuring: Evidence for individual industries

    SciTech Connect

    Costello, K.W.; Graniere, R.J.

    1997-05-01

    Several studies have measured the effects of regulation on a particular industry. These studies range widely in sophistication, from simple observation (comparison) of pre-transformation and post-transformation actual industry performance to econometric analysis that attempt to separate the effects of deregulation from other factors in explaining changes in an industry`s performance. The major problem with observation studies is that they are unable to measure the effect of one particular event, such as deregulation, on an industry`s performance. For example, at the same time that the United Kingdom privatized its electric power industry, it also radically restructured the industry to encourage competition and instituted a price-cap mechanism to regulate the prices of transmission, distribution, and bundled retail services. Subsequent to these changes in 1991, real prices for most UK electricity customers have fallen. It is not certain however, which of these factors was most important or even contributed to the decline in price. In any event, one must be cautious in interpreting the results of studies that attempt to measure the effect of deregulation per se for a specific industry. This report highlights major outcomes for five industries undergoing deregulation or major regulatory and restructuring reforms. These include the natural gas, transportation, UK electric power, financial, and telecommunications industries. Particular attention was given to the historical development of events in the telecommunications industry.

  3. The interaction of AGT and NOS3 gene polymorphisms with conventional risk factors increases predisposition to hypertension.

    PubMed

    Gatti, Renata R; Santos, Paula S; Sena, Angela A S; Marangoni, Karina; Araújo, Messias A; Goulart, Luiz R

    2013-12-01

    Renin-angiotensin and kallikrein-kinin systems are interconnected, regulating blood pressure homeostasis. We have demonstrated the interactions among polymorphisms of the angiotensinogen (AGT) and endothelial nitric oxide synthase (NOS3) genes and conventional risk factors affecting the hypertension occurrence. Individuals were recruited (n=192) and classified into hypertensive (HG; n=140) and normotensive (NG; n=52) groups. The genotypic distribution of the Met235Thr (AGT) and Glu298Asp (NOS3) polymorphisms demonstrated that both are independent risk factors of hypertension (p=0.02 and p=0.008, respectively). The concomitant presence of these polymorphisms in the HG group was significantly different (p=0.001) from the NG. Both gene polymorphisms presented an additive effect for the unfavourable alleles T and A, respectively, and 95% of the double mutant homozygotes were classified into the HG. Specific interactions among certain conventional factors and the presence of at least one unfavourable allele presented significant odds towards hypertension. Blood pressure homeostasis was affected by genetic polymorphisms conditioned by the T and A alleles of the AGT and NOS3 genes, respectively, which acted independently. However, their interaction with smoking, sedentariness, age and total cholesterol may have increased the predisposition to hypertension, which may explain most of the hypertension cases. PMID:22791701

  4. Novel regulation of Skp1 by the Dictyostelium AgtA α-galactosyltransferase involves the Skp1-binding activity of its WD40 repeat domain.

    PubMed

    Schafer, Christopher M; Sheikh, M Osman; Zhang, Dongmei; West, Christopher M

    2014-03-28

    The role of Skp1 as an adaptor protein that links Cullin-1 to F-box proteins in E3 Skp1/Cullin-1/F-box protein (SCF) ubiquitin ligases is well characterized. In the social amoeba Dictyostelium and probably many other unicellular eukaryotes, Skp1 is modified by a pentasaccharide attached to a hydroxyproline near its C terminus. This modification is important for oxygen-sensing during Dictyostelium development and is mediated by a HIF-α type prolyl 4-hydroxylase and five sequentially acting cytoplasmic glycosyltransferase activities. Gene disruption studies show that AgtA, the enzyme responsible for addition of the final two galactose residues, in α-linkages to the Skp1 core trisaccharide, is unexpectedly critical for oxygen-dependent terminal development. AgtA possesses a WD40 repeat domain C-terminal to its single catalytic domain and, by use of domain deletions, binding studies, and enzyme assays, we find that the WD40 repeats confer a salt-sensitive second-site binding interaction with Skp1 that mediates novel catalytic activation in addition to simple substrate recognition. In addition, AgtA binds similarly well to precursor isoforms of Skp1 by a salt-sensitive mechanism that competes with binding to an F-box protein and recognition by early modification enzymes, and the effect of binding is diminished when AgtA modifies Skp1. Genetic studies show that loss of AgtA is more severe when an earlier glycosylation step is blocked, and overexpressed AgtA is deleterious if catalytically inactivated. Together, the findings suggest that AgtA mediates non-enzymatic control of unmodified and substrate precursor forms of Skp1 by a binding mechanism that is normally relieved by switch-like activation of its glycosylation function. PMID:24550398

  5. Transcriptional Control of Mitosis: Deregulation and Cancer

    PubMed Central

    Nath, Somsubhra; Ghatak, Dishari; Das, Pijush; Roychoudhury, Susanta

    2015-01-01

    Research over the past few decades has well established the molecular functioning of mitosis. Deregulation of these functions has also been attributed to the generation of aneuploidy in different tumor types. Numerous studies have given insight into the regulation of mitosis by cell cycle specific proteins. Optimum abundance of these proteins is pivotal to timely execution of mitosis. Aberrant expressions of these mitotic proteins have been reported in different cancer types. Several post-transcriptional mechanisms and their interplay have subsequently been identified that control the level of mitotic proteins. However, to date, infrequent incidences of cancer-associated mutations have been reported for the genes expressing these proteins. Therefore, altered expression of these mitotic regulators in tumor samples can largely be attributed to transcriptional deregulation. This review discusses the biology of transcriptional control for mitosis and evaluates its role in the generation of aneuploidy and tumorigenesis. PMID:25999914

  6. Deregulation of Cell Signaling in Cancer

    PubMed Central

    Giancotti, Filippo G.

    2014-01-01

    Summary Oncogenic mutations disrupt the regulatory circuits that govern cell function, enabling tumor cells to undergo de-regulated mitogenesis, to resist to proapoptotic insults, and to invade through tissue boundaries. Cancer cell biology has played a crucial role in elucidating the signaling mechanisms by which oncogenic mutations sustain these malignant behaviors and thereby in identifying rational targets for cancer drugs. The efficacy of such targeted therapies illustrate the power of a reductionist approach to the study of cancer. PMID:24561200

  7. Air pollution effects due to deregulation of the electric industry

    NASA Astrophysics Data System (ADS)

    Davoodi, Khojasteh Riaz

    The Energy Policy Act of 1992 introduced the concept of open-access into the electric utility industry which allows privately-owned utilities to transmit power produced by non-utility generators and independent power producers (IPPs). In April 1996, the Federal Energy Regulatory Commission (FERC) laid down the final rules (Orders No. 888 & No. 889), which required utilities to open their transmission lines to any power producer and charge them no more than what they pay for the use of their own lines. These rules set the stage for the retail sale of electricity to industrial, commercial and residential utility customers; non-utility generators (Nugs); and power marketers. These statutory, regulatory and administrative changes create for the electric utility industry two different forces that contradict each other. The first is the concept of competition among utility companies; this places a greater emphasis on electric power generation cost control and affects generation/fuel mix selection and demand side management (DSM) activities. The second force, which is converse to the first, is that utilities are major contributors to the air pollution burden in the United States and environmental concerns are forcing them to reduce emissions of air pollutants by using more environmentally friendly fuels and implementing energy saving programs. This study evaluates the impact of deregulation within the investor owned electric utilities and how this deregulation effects air quality by investigating the trend in demand side management programs and generation/fuel mix. A survey was conducted of investor owned utilities and independent power producers. The results of the survey were analyzed by analysis of variance and regression analysis to determine the impact to Air Pollution. An air Quality Impact model was also developed in this study. This model consists of six modules: (1) demand side management and (2) consumption of coal, (3) gas, (4) renewable, (5) oil and (6

  8. CYP1A1, GCLC, AGT, AGTR1 gene-gene interactions in community-acquired pneumonia pulmonary complications.

    PubMed

    Salnikova, Lyubov E; Smelaya, Tamara V; Golubev, Arkadiy M; Rubanovich, Alexander V; Moroz, Viktor V

    2013-11-01

    This study was conducted to establish the possible contribution of functional gene polymorphisms in detoxification/oxidative stress and vascular remodeling pathways to community-acquired pneumonia (CAP) susceptibility in the case-control study (350 CAP patients, 432 control subjects) and to predisposition to the development of CAP complications in the prospective study. All subjects were genotyped for 16 polymorphic variants in the 14 genes of xenobiotics detoxification CYP1A1, AhR, GSTM1, GSTT1, ABCB1, redox-status SOD2, CAT, GCLC, and vascular homeostasis ACE, AGT, AGTR1, NOS3, MTHFR, VEGFα. Risk of pulmonary complications (PC) in the single locus analysis was associated with CYP1A1, GCLC and AGTR1 genes. Extra PC (toxic shock syndrome and myocarditis) were not associated with these genes. We evaluated gene-gene interactions using multi-factor dimensionality reduction, and cumulative gene risk score approaches. The final model which included >5 risk alleles in the CYP1A1 (rs2606345, rs4646903, rs1048943), GCLC, AGT, and AGTR1 genes was associated with pleuritis, empyema, acute respiratory distress syndrome, all PC and acute respiratory failure (ARF). We considered CYP1A1, GCLC, AGT, AGTR1 gene set using Set Distiller mode implemented in GeneDecks for discovering gene-set relations via the degree of sharing descriptors within a given gene set. N-acetylcysteine and oxygen were defined by Set Distiller as the best descriptors for the gene set associated in the present study with PC and ARF. Results of the study are in line with literature data and suggest that genetically determined oxidative stress exacerbation may contribute to the progression of lung inflammation.

  9. Deregulation of Rho GTPases in cancer

    PubMed Central

    Porter, Andrew P.; Papaioannou, Alexandra; Malliri, Angeliki

    2016-01-01

    ABSTRACT In vitro and in vivo studies and evidence from human tumors have long implicated Rho GTPase signaling in the formation and dissemination of a range of cancers. Recently next generation sequencing has identified direct mutations of Rho GTPases in human cancers. Moreover, the effects of ablating genes encoding Rho GTPases and their regulators in mouse models, or through pharmacological inhibition, strongly suggests that targeting Rho GTPase signaling could constitute an effective treatment. In this review we will explore the various ways in which Rho signaling can be deregulated in human cancers. PMID:27104658

  10. Energy flow for electric power system deregulation

    NASA Astrophysics Data System (ADS)

    Lin, Chia-Hung

    Over the past few years, the electric power utility industry in North America and other countries has experienced a strong drive towards deregulation. People have considered the necessity of deregulation of electric utilities for higher energy efficiency and energy saving. The vertically integrated monopolistic industry is being transferred into a horizontally integrated competitive structure in some countries. Wheeling charges are a current high priority problem throughout the power industry, for independent power producers, as well as regulators. Nevertheless the present transmission pricing mechanism fails to be adjusted by a customer loading condition. Customer loading is dynamic, but the present wheeling charge method is fixed, not real-time. A real-time wheeling charge method is developed in this dissertation. This dissertation introduces a concept of a power flow network which can be used for the calculation of power contribution factors in a network. The contribution factor is defined as the ratio of the power contributed by a particular source to a line flow or bus load to the total output of the source. Generation, transmission, and distribution companies can employ contribution factors for the calculation of energy cost, wheeling charges, and loss compensation. Based on the concept of contribution factors, a proposed loss allocation method is developed in this dissertation. Besides, counterflow condition will be given a credit in the proposed loss allocation method. A simple 22-bus example was used for evaluating the contribution factors, proposed wheeling charge method, and loss allocation method.

  11. Deregulated proliferation and differentiation in brain tumors

    PubMed Central

    Swartling, Fredrik J; Čančer, Matko; Frantz, Aaron; Weishaupt, Holger; Persson, Anders I

    2014-01-01

    Neurogenesis, the generation of new neurons, is deregulated in neural stem cell (NSC)- and progenitor-derived murine models of malignant medulloblastoma and glioma, the most common brain tumors of children and adults, respectively. Molecular characterization of human malignant brain tumors, and in particular brain tumor stem cells (BTSCs), has identified neurodevelopmental transcription factors, microRNAs, and epigenetic factors known to inhibit neuronal and glial differentiation. We are starting to understand how these factors are regulated by the major oncogenic drivers in malignant brain tumors. In this review, we will focus on the molecular switches that block normal neuronal differentiation and induce brain tumor formation. Genetic or pharmacological manipulation of these switches in BTSCs has been shown to restore the ability of tumor cells to differentiate. We will discuss potential brain tumor therapies that will promote differentiation in order to reduce treatment-resistance, suppress tumor growth, and prevent recurrence in patients. PMID:25416506

  12. Caenorhabditis elegans AGXT-1 is a mitochondrial and temperature-adapted ortholog of peroxisomal human AGT1: New insights into between-species divergence in glyoxylate metabolism.

    PubMed

    Mesa-Torres, Noel; Calvo, Ana C; Oppici, Elisa; Titelbaum, Nicholas; Montioli, Riccardo; Miranda-Vizuete, Antonio; Cellini, Barbara; Salido, Eduardo; Pey, Angel L

    2016-09-01

    In humans, glyoxylate is an intermediary product of metabolism, whose concentration is finely balanced. Mutations in peroxisomal alanine:glyoxylate aminotransferase (hAGT1) cause primary hyperoxaluria type 1 (PH1), which results in glyoxylate accumulation that is converted to toxic oxalate. In contrast, glyoxylate is used by the nematode Caenorhabditis elegans through a glyoxylate cycle to by-pass the decarboxylation steps of the tricarboxylic acid cycle and thus contributing to energy production and gluconeogenesis from stored lipids. To investigate the differences in glyoxylate metabolism between humans and C. elegans and to determine whether the nematode might be a suitable model for PH1, we have characterized here the predicted nematode ortholog of hAGT1 (AGXT-1) and compared its molecular properties with those of the human enzyme. Both enzymes form active PLP-dependent dimers with high specificity towards alanine and glyoxylate, and display similar three-dimensional structures. Interestingly, AGXT-1 shows 5-fold higher activity towards the alanine/glyoxylate pair than hAGT1. Thermal and chemical stability of AGXT-1 is lower than that of hAGT1, suggesting temperature-adaptation of the nematode enzyme linked to the lower optimal growth temperature of C. elegans. Remarkably, in vivo experiments demonstrate the mitochondrial localization of AGXT-1 in contrast to the peroxisomal compartmentalization of hAGT1. Our results support the view that the different glyoxylate metabolism in the nematode is associated with the divergent molecular properties and subcellular localization of the alanine:glyoxylate aminotransferase activity.

  13. Caenorhabditis elegans AGXT-1 is a mitochondrial and temperature-adapted ortholog of peroxisomal human AGT1: New insights into between-species divergence in glyoxylate metabolism.

    PubMed

    Mesa-Torres, Noel; Calvo, Ana C; Oppici, Elisa; Titelbaum, Nicholas; Montioli, Riccardo; Miranda-Vizuete, Antonio; Cellini, Barbara; Salido, Eduardo; Pey, Angel L

    2016-09-01

    In humans, glyoxylate is an intermediary product of metabolism, whose concentration is finely balanced. Mutations in peroxisomal alanine:glyoxylate aminotransferase (hAGT1) cause primary hyperoxaluria type 1 (PH1), which results in glyoxylate accumulation that is converted to toxic oxalate. In contrast, glyoxylate is used by the nematode Caenorhabditis elegans through a glyoxylate cycle to by-pass the decarboxylation steps of the tricarboxylic acid cycle and thus contributing to energy production and gluconeogenesis from stored lipids. To investigate the differences in glyoxylate metabolism between humans and C. elegans and to determine whether the nematode might be a suitable model for PH1, we have characterized here the predicted nematode ortholog of hAGT1 (AGXT-1) and compared its molecular properties with those of the human enzyme. Both enzymes form active PLP-dependent dimers with high specificity towards alanine and glyoxylate, and display similar three-dimensional structures. Interestingly, AGXT-1 shows 5-fold higher activity towards the alanine/glyoxylate pair than hAGT1. Thermal and chemical stability of AGXT-1 is lower than that of hAGT1, suggesting temperature-adaptation of the nematode enzyme linked to the lower optimal growth temperature of C. elegans. Remarkably, in vivo experiments demonstrate the mitochondrial localization of AGXT-1 in contrast to the peroxisomal compartmentalization of hAGT1. Our results support the view that the different glyoxylate metabolism in the nematode is associated with the divergent molecular properties and subcellular localization of the alanine:glyoxylate aminotransferase activity. PMID:27179589

  14. Regulation and deregulation of natural gas in the US: 1938-1985

    SciTech Connect

    Merrill, Peter R.

    1980-06-01

    Public policy towards natural gas has swung first towards, and then away from regulation in this century. In 1906, the Congress specifically excluded natural gas from the jurisdiction of the Interstate Commerce Commission. Three decades later, a New Deal Congress passed the Natural Gas Act of 1938 bringing pipelines under the control of the Federal Power Commission (FDC). Forty years thereafter, the Congress passed a phased decontrol bill, the Natural Gas Policy Act (NGPA) of 1978, as part of the Carter Administration's National Energy Plan. Recently, the Congress has backed off from New Deal legislation in other markets - notably aviation and trucking. In this study, the rise and fall of economic regulation in the natural gas industry are examined to understand: (1) why public policy has followed a pendulum's path, and (2) the economic consequences of regulation and deregulation. The main part of the analysis is directed toward the Natural Gas Policy Act of 1978. Widely viewed as a deregulation measure, the author finds that the Act is more restrictive and burdensome than the pricing policies it superceded. The path toward deregulation in natural gas and perhaps other markets is not as direct or simple as might be expected.

  15. Efficiency in the United States electric industry: Transaction costs, deregulation, and governance structures

    NASA Astrophysics Data System (ADS)

    Peterson, Carl

    Transaction costs economics (TCE) posits that firms have an incentive to bypass the market mechanisms in situations where the cost of using the market is prohibitive. Vertical integration, among other governance mechanisms, can be used to minimize the transactions costs associated with the market mechanism. The study analyses different governance mechanisms, which range from complete vertical integration to the use of market mechanisms, for firms in the US electric sector. This sector has undergone tremendous change in the past decade including the introduction of retail competition in some jurisdictions. As a result of the push toward deregulation of the industry, vertically integration, while still significant in the sector, has steadily been replaced by alternative governance structures. Using a sample of 136 investor-owned electric utilities that reported data the US Federal Energy Regulatory Commission between 1996 and 2002, this study estimates firm level efficiency using Data Envelopment Analysis (DEA) and relates these estimates to governance structure and public policies. The analysis finds that vertical integration is positively related to firm efficiency, although in a non-linear fashion suggesting that hybrid governance structures tend to be associated with lower efficiency scores. In addition, while some evidence is found for negative short-term effects on firm efficiency from the choice to deregulate, this result is sensitive to DEA model choice. Further, competition in retail markets is found to be positively related to firm level efficiency, but the retreat from deregulation, which occurred after 2000, is negatively associated with firm-level efficiency. These results are important in the ongoing academic and public policy debates concerning deregulation of the electric section and indicate that vertical economies remain in the industry, but that competition has provided incentives for improving firm level efficiency.

  16. Deregulation and Nuclear Training: Cost Effective Alternatives

    SciTech Connect

    Richard P. Coe; Patricia A. Lake

    2000-11-12

    Training is crucial to the success of any organization. It is also expensive, with some estimates exceeding $50 billion annually spent on training by U.S. corporations. Nuclear training, like that of many other highly technical organizations, is both crucial and costly. It is unlikely that the amount of training can be significantly reduced. If anything, current trends indicate that training needs will probably increase as the industry and workforce ages and changes. With the advent of energy deregulation in the United States, greater pressures will surface to make the costs of energy more cost-competitive. This in turn will drive businesses to more closely examine existing costs and find ways to do things in a more cost-effective way. The commercial nuclear industry will be no exception, and nuclear training will be equally affected. It is time for nuclear training and indeed the entire nuclear industry to begin using more aggressive techniques to reduce costs. This includes the need for nuclear training to find alternatives to traditional methods for the delivery of cost-effective high-quality training that meets regulatory requirements and produces well-qualified personnel capable of working in an efficient and safe manner. Computer-based and/or Web-based training are leading emerging technologies.

  17. Epigenetic deregulation in pediatric acute lymphoblastic leukemia

    PubMed Central

    Chatterton, Zac; Morenos, Leah; Mechinaud, Francoise; Ashley, David M; Craig, Jeffrey M; Sexton-Oates, Alexandra; Halemba, Minhee S; Parkinson-Bates, Mandy; Ng, Jane; Morrison, Debra; Carroll, William L; Saffery, Richard; Wong, Nicholas C

    2014-01-01

    Similar to most cancers, genome-wide DNA methylation profiles are commonly altered in pediatric acute lymphoblastic leukemia (ALL); however, recent observations highlight that a large portion of malignancy-associated DNA methylation alterations are not accompanied by related gene expression changes. By analyzing and integrating the methylome and transcriptome profiles of pediatric B-cell ALL cases and primary tissue controls, we report 325 genes hypermethylated and downregulated and 45 genes hypomethylated and upregulated in pediatric B-cell ALL, irrespective of subtype. Repressed cation channel subunits and cAMP signaling activators and transducers are overrepresented, potentially indicating a reduced cellular potential to receive and propagate apoptotic signals. Furthermore, we report specific DNA methylation alterations with concurrent gene expression changes within individual ALL subtypes. The ETV6-RUNX1 translocation was associated with downregulation of ASNS and upregulation of the EPO-receptor, while Hyperdiploid patients (>50 chr) displayed upregulation of B-cell lymphoma (BCL) members and repression of PTPRG and FHIT. In combination, these data indicate genetically distinct B-cell ALL subtypes contain cooperative epimutations and genome-wide epigenetic deregulation is common across all B-cell ALL subtypes. PMID:24394348

  18. Understanding electricity market reforms and the case of Philippine deregulation

    SciTech Connect

    Santiago, Andrea; Roxas, Fernando

    2010-03-15

    The experience of the Philippines offers lessons that should be relevant to any country seeking to deregulate its power industry. Regardless of structure, consumers must face the real price of electricity production and delivery that is closer to marginal cost. Politically motivated prices merely shift the burden from ratepayers to taxpayers. And any reform should work within a reasonable timetable. (author)

  19. Evaluating an Ice-Storage System in a Deregulated Environment.

    ERIC Educational Resources Information Center

    Staniewicz, Theodore J.; Watson, Joseph J.

    2001-01-01

    Examines the difficulties the electric industry's deregulation created for St. Joseph's University's (Philadelphia) development of a thermal ice-storage system as part of its HVAC design and the school's solution. A monthly equipment summary sheet with year-to-date figures is provided. (GR)

  20. Epigenetic deregulation of the COX pathway in cancer.

    PubMed

    Cebola, Inês; Peinado, Miguel A

    2012-10-01

    Inflammation is a major cause of cancer and may condition its progression. The deregulation of the cyclooxygenase (COX) pathway is implicated in several pathophysiological processes, including inflammation and cancer. Although, its targeting with nonsteroidal antiinflammatory drugs (NSAIDs) and COX-2 selective inhibitors has been investigated for years with promising results at both preventive and therapeutic levels, undesirable side effects and the limited understanding of the regulation and functionalities of the COX pathway compromise a more extensive application of these drugs. Epigenetics is bringing additional levels of complexity to the understanding of basic biological and pathological processes. The deregulation of signaling and biosynthetic pathways by epigenetic mechanisms may account for new molecular targets in cancer therapeutics. Genes of the COX pathway are seldom mutated in neoplastic cells, but a large proportion of them show aberrant expression in different types of cancer. A growing body of evidence indicates that epigenetic alterations play a critical role in the deregulation of the genes of the COX pathway. This review summarizes the current knowledge on the contribution of epigenetic processes to the deregulation of the COX pathway in cancer, getting insights into how these alterations may be relevant for the clinical management of patients. PMID:22580191

  1. U.S. Broadcast Deregulation: A Case of Dubious Evidence.

    ERIC Educational Resources Information Center

    Levin, Harry J.

    1986-01-01

    Reviews the empirical evidence cited by the FCC in favor of increasing the allowable number of radio and TV stations owned by one group. Argues FCC was biased in favor of deregulation despite weighty evidence indicating continued need for regulation. (MS)

  2. Electric Restructuring and Utilities Deregulation: A Facility Manager's Guide.

    ERIC Educational Resources Information Center

    Glazner, Steve, Ed.

    This volume presents 12 papers offering guidelines to higher education institutions on planning for the deregulation of the electric power industry. Following an introduction (by Dorsey D. Jacobs), the papers are organized into three parts which address: the changing market, identifying opportunities and challenges, and taking advantage of…

  3. Deregulation of University Education in Nigeria: Problems and Prospects

    ERIC Educational Resources Information Center

    Adeogun, A. A.; Subair, S. T.; Osifila, G. I.

    2009-01-01

    This paper focuses on the deregulation of university education in Nigeria, its problems and prospects. The paper commences with the recognition given to education all over the world, especially higher education. Nigeria as a country gives much credence to higher education as the means for social and economic mobility, social transformation, and as…

  4. Telecommunications Policy Research Conference. Broadcast Deregulation Section. Papers.

    ERIC Educational Resources Information Center

    Telecommunications Policy Research Conference, Inc., Washington, DC.

    Two papers presented in the broadcast deregulation section analyze narrowcasting and the effects of commercialization of British television respectively. The first paper, "The American Model through British Eyes" (Jay G. Blumler and Carolyn Spicer), describes research undertaken at the request of the British government-appointed "Peacock…

  5. Epistatic interaction between common AGT G(-6)A (rs5051) and AGTR1 A1166C (rs5186) variants contributes to variation in kidney size at birth.

    PubMed

    Kaczmarczyk, Mariusz; Kuprjanowicz, Anna; Łoniewska, Beata; Gorący, Iwona; Taryma-Leśniak, Olga; Skonieczna-Żydecka, Karolina; Ciechanowicz, Andrzej

    2015-11-01

    Low nephron number has been recognised as an important cardiovascular risk factor and recently a strong correlation between renal mass and nephron number has been demonstrated in newborns. The aim of this study was to investigate individual, as well as combined, effects of common variants of genes which encode for major components of the renin-angiotensin system (REN G10601A, AGT G(-6)A, ACE I/D, AGTR1 A1166C) on kidney size in healthy, full-term newborns. A significant additive main effect of the ACE I/D polymorphism, as well as an additive-by-additive interaction between AGT G(-6)A and AGTR1 A1166C variants, were found. The variance attributed to the epistatic effect was 27.9 ml(2)/m(4), which accounted for 73.8% of the interaction variance (37.8 ml(2)/m(4)), 66.4% of the genetic variance (42.0 ml(2)/m(4)) and 4.4% to the total phenotypic variance (628 ml(2)/m(4)). No other statistically significant main or epistatic effects were detected. Our results highlight the importance of considering gene-gene interactions as part of the genetic architecture of congenital nephron number, even when the loci do not show significant single locus effects. Unravelling the genetic determinants of low nephron number, along with early molecular screening, may well help to identify children at risk for cardiovascular disease.

  6. Customer choice: Purchasing energy in a deregulated market

    SciTech Connect

    Thumann, A.

    1999-09-01

    This book presents the detailed guidance on how to effectively purchase deregulated energy, based on first-hand reports from many of the nation`s most knowledgeable experts. It is designed to provide the kind of practical advice needed by professionals who are responsible for making energy purchasing decisions. The book gives a ten-step program to guide building owners in purchasing decision making, a state-by-state retail competition update, and guidelines for buying electricity and natural gas over the worldwide web. Other topics include contract renegotiation strategies, an assessment of power pools, the role of aggregators in the energy market, real time pricing issues, where cogeneration fits within today`s marketplace, and lessons learned from deregulation experiences in Scandinavia and England.

  7. A model for gene deregulation detection using expression data

    PubMed Central

    2015-01-01

    In tumoral cells, gene regulation mechanisms are severely altered. Genes that do not react normally to their regulators' activity can provide explanations for the tumoral behavior, and be characteristic of cancer subtypes. We thus propose a statistical methodology to identify the misregulated genes given a reference network and gene expression data. Our model is based on a regulatory process in which all genes are allowed to be deregulated. We derive an EM algorithm where the hidden variables correspond to the status (under/over/normally expressed) of the genes and where the E-step is solved thanks to a message passing algorithm. Our procedure provides posterior probabilities of deregulation in a given sample for each gene. We assess the performance of our method by numerical experiments on simulations and on a bladder cancer data set. PMID:26679516

  8. Generation capacity expansion planning in deregulated electricity markets

    NASA Astrophysics Data System (ADS)

    Sharma, Deepak

    With increasing demand of electric power in the context of deregulated electricity markets, a good strategic planning for the growth of the power system is critical for our tomorrow. There is a need to build new resources in the form of generation plants and transmission lines while considering the effects of these new resources on power system operations, market economics and the long-term dynamics of the economy. In deregulation, the exercise of generation planning has undergone a paradigm shift. The first stage of generation planning is now undertaken by the individual investors. These investors see investments in generation capacity as an increasing business opportunity because of the increasing market prices. Therefore, the main objective of such a planning exercise, carried out by individual investors, is typically that of long-term profit maximization. This thesis presents some modeling frameworks for generation capacity expansion planning applicable to independent investor firms in the context of power industry deregulation. These modeling frameworks include various technical and financing issues within the process of power system planning. The proposed modeling frameworks consider the long-term decision making process of investor firms, the discrete nature of generation capacity addition and incorporates transmission network modeling. Studies have been carried out to examine the impact of the optimal investment plans on transmission network loadings in the long-run by integrating the generation capacity expansion planning framework within a modified IEEE 30-bus transmission system network. The work assesses the importance of arriving at an optimal IRR at which the firm's profit maximization objective attains an extremum value. The mathematical model is further improved to incorporate binary variables while considering discrete unit sizes, and subsequently to include the detailed transmission network representation. The proposed models are novel in the

  9. Managing an evolution: Deregulation of the electric utility industry

    SciTech Connect

    Skinner, S.K.

    1994-12-31

    The author discusses the emerging competitive situation in the electric power industry as deregulation of electric utilities looms on the horizon. The paper supports this change, and the competition it will bring, but urges caution as changes are instituted, and the regulatory bodies decide how and how much to free, and at what rates. The reason for his urge for caution comes from historical experience of other industries, which were smaller and had less direct impact on every American.

  10. Advanced Gas Turbine (AGT)

    NASA Technical Reports Server (NTRS)

    1983-01-01

    The development and progress of the Advanced Gas Turbine engine program is examined. An analysis of the role of ceramics in the design and major engine components is included. Projected fuel economy, emissions and performance standards, and versatility in fuel use are also discussed.

  11. Power systems locational marginal pricing in deregulated markets

    NASA Astrophysics Data System (ADS)

    Wang, Hui-Fung Francis

    Since the beginning of the 1990s, the electricity business is transforming from a vertical integrating business to a competitive market operations. The generation, transmission, distribution subsystem of an electricity utility are operated independently as Genco (generation subsystem), Transco (transmission subsystem), and Distco (distribution subsystem). This trend promotes more economical inter- and intra regional transactions to be made by the participating companies and the users of electricity to achieve the intended objectives of deregulation. There are various types of electricity markets that are implemented in the North America in the past few years. However, transmission congestion management becomes a key issue in the electricity market design as more bilateral transactions are traded across long distances competing for scarce transmission resources. It directly alters the traditional concept of energy pricing and impacts the bottom line, revenue and cost of electricity, of both suppliers and buyers. In this research, transmission congestion problem in a deregulated market environment is elucidated by implementing by the Locational Marginal Pricing (LMP) method. With a comprehensive understanding of the LMP method, new mathematical tools will aid electric utilities in exploring new business opportunities are developed and presented in this dissertation. The dissertation focuses on the development of concept of (LMP) forecasting and its implication to the market participants in deregulated market. Specifically, we explore methods of developing fast LMP calculation techniques that are differ from existing LMPs. We also explore and document the usefulness of the proposed LMP in determining electricity pricing of a large scale power system. The developed mathematical tools use of well-known optimization techniques such as linear programming that are support by several flow charts. The fast and practical security constrained unit commitment methods are the

  12. Natural flavonoids targeting deregulated cell cycle progression in cancer cells.

    PubMed

    Singh, Rana Pratap; Agarwal, Rajesh

    2006-03-01

    The prolonged duration requiring alteration of multi-genetic and epigenetic molecular events for cancer development provides a strong rationale for cancer prevention, which is developing as a potential strategy to arrest or reverse carcinogenic changes before the appearance of the malignant disease. Cell cycle progression is an important biological event having controlled regulation in normal cells, which almost universally becomes aberrant or deregulated in transformed and neoplastic cells. In this regard, targeting deregulated cell cycle progression and its modulation by various natural and synthetic agents are gaining widespread attention in recent years to control the unchecked growth and proliferation in cancer cells. In fact, a vast number of experimental studies convincingly show that many phytochemicals halt uncontrolled cell cycle progression in cancer cells. Among these phytochemicals, natural flavonoids have been identified as a one of the major classes of natural anticancer agents exerting antineoplastic activity via cell cycle arrest as a major mechanism in various types of cancer cells. This review is focused at the modulatory effects of natural flavonoids on cell cycle regulators including cyclin-dependent kinases and their inhibitors, cyclins, p53, retinoblastoma family of proteins, E2Fs, check-point kinases, ATM/ATR and survivin controlling G1/S and G2/M check-point transitions in cell cycle progression, and discusses how these molecular changes could contribute to the antineoplastic effects of natural flavonoids.

  13. Artificial intelligence methods in deregulated power systems operations

    NASA Astrophysics Data System (ADS)

    Ilic, Jovan

    With the introduction of the power systems deregulation, many classical power transmission and distribution optimization tools became inadequate. Optimal Power Flow and Unit Commitment are common computer programs used in the regulated power industry. This work is addressing the Optimal Power Flow and Unit Commitment in the new deregulated environment. Optimal Power Flow is a high dimensional, non-linear, and non-convex optimization problem. As such, it is even now, after forty years since its introduction, a research topic without a widely accepted solution able to encompass all areas of interest. Unit Commitment is a high dimensional, combinatorial problem which should ideally include the Optimal Power Flow in its solution. The dimensionality of a typical Unit Commitment problem is so great that even the enumeration of all the combinations would take too much time for any practical purposes. This dissertation attacks the Optimal Power Flow problem using non-traditional tools from the Artificial Intelligence arena. Artificial Intelligence optimization methods are based on stochastic principles. Usually, stochastic optimization methods are successful where all other classical approaches fail. We will use Genetic Programming optimization for both Optimal Power Flow and Unit Commitment. Long processing times will also be addressed through supervised machine learning.

  14. Cell cycle deregulation by methyl isocyanate: Implications in liver carcinogenesis.

    PubMed

    Panwar, Hariom; Raghuram, Gorantla V; Jain, Deepika; Ahirwar, Alok K; Khan, Saba; Jain, Subodh K; Pathak, Neelam; Banerjee, Smita; Maudar, Kewal K; Mishra, Pradyumna K

    2014-03-01

    Liver is often exposed to plethora of chemical toxins. Owing to its profound physiological role and central function in metabolism and homeostasis, pertinent succession of cell cycle in liver epithelial cells is of prime importance to maintain cellular proliferation. Although recent evidence has displayed a strong association between exposures to methyl isocyanate (MIC), one of the most toxic isocyanates, and neoplastic transformation, molecular characterization of the longitudinal effects of MIC on cell cycle regulation has never been performed. Here, we sequentially delineated the status of different proteins arbitrating the deregulation of cell cycle in liver epithelial cells treated with MIC. Our data reaffirms the oncogenic capability of MIC with elevated DNA damage response proteins pATM and γ-H2AX, deregulation of DNA damage check point genes CHK1 and CHK2, altered expression of p53 and p21 proteins involved in cell cycle arrest with perturbation in GADD-45 expression in the treated cells. Further, alterations in cyclin A, cyclin E, CDK2 levels along with overexpression of mitotic spindle checkpoints proteins Aurora A/B, centrosomal pericentrin protein, chromosomal aberrations, and loss of Pot1a was observed. Thus, MIC impacts key proteins involved in cell cycle regulation to trigger genomic instability as a possible mechanism of developmental basis of liver carcinogenesis.

  15. Steady state security assessment in deregulated power systems

    NASA Astrophysics Data System (ADS)

    Manjure, Durgesh Padmakar

    Power system operations are undergoing changes, brought about primarily due to deregulation and subsequent restructuring of the power industry. The primary intention of the introduction of deregulation in power systems was to bring about competition and improved customer focus. The underlying motive was increased economic benefit. Present day power system analysis is much different than what it was earlier, essentially due to the transformation of the power industry from being cost-based to one that is price-based and due to open access of transmission networks to the various market participants. Power is now treated as a commodity and is traded in an open market. The resultant interdependence of the technical criteria and the economic considerations has only accentuated the need for accurate analysis in power systems. The main impetus in security analysis studies is on efficient assessment of the post-contingency status of the system, accuracy being of secondary consideration. In most cases, given the time frame involved, it is not feasible to run a complete AC load flow for determining the post-contingency state of the system. Quite often, it is not warranted as well, as an indication of the state of the system is desired rather than the exact quantification of the various state variables. With the inception of deregulation, transmission networks are subjected to a host of multilateral transactions, which would influence physical system quantities like real power flows, security margins and voltage levels. For efficient asset utilization and maximization of the revenue, more often than not, transmission networks are operated under stressed conditions, close to security limits. Therefore, a quantitative assessment of the extent to which each transaction adversely affects the transmission network is required. This needs to be done accurately as the feasibility of the power transactions and subsequent decisions (execution, curtailment, pricing) would depend upon the

  16. Monitoring receptor trafficking following retromer and WASH deregulation.

    PubMed

    Osborne, Douglas G; Phillips-Krawczak, Christine A; Billadeau, Daniel D

    2015-01-01

    Cell surface receptors that have been internalized and enter the endocytic pathway have multiple fates including entrance into the multivesicular body pathway on their way to lysosomal degradation, recycling back to the cell surface, or retrograde trafficking out of the endolysosomal system back to the Golgi apparatus. Two ubiquitously expressed protein complexes, WASH and the endosomal coat complex retromer, function together to play a central role in directing the fate of receptors into the latter two pathways. In this chapter, we describe fluorescent- and flow cytometry-based methods for analyzing the recycling and retrograde trafficking of two receptors, α5β1 and CI-M6PR, whose intracellular fates are regulated by WASH and retromer activity. The guidelines presented in this chapter can be applied to the analysis of any cell surface or intracellular membrane protein to determine the impact of WASH or retromer deregulation on its intracellular trafficking route. PMID:26360036

  17. Market Model Considering Bilateral Transactions in the Deregulated Electricity Market

    NASA Astrophysics Data System (ADS)

    Ruiz Monroy, José Joaquín; Kita, Hiroyuki; Tanaka, Eiichi; Hasegawa, Jun

    This paper proposes an algorithm to simulate the transactions that take place in a free market of electricity. The algorithm presented is used for Bilateral Transaction Matrix (BTM) creation assuming that a day ahead load forecast is previously known. Bids can be made by both the generation side and the demand side to determine transaction prices, then the algorithm allocates the transactions according to market rules until the demand is satisfied. This creates feasible BTMs that can be used to study system security and to find future methods to regulate bilateral transactions through market mechanisms like the application of penalties to the transactions that affect the system’s security. Results show that the proposed algorithm is a good option for electricity market analysis. The proposed algorithm provides system planners with a practical tool for data creation to further study the effects of bilateral transactions in a deregulated electricity market.

  18. Voltage stability analysis in the new deregulated environment

    NASA Astrophysics Data System (ADS)

    Zhu, Tong

    Nowadays, a significant portion of the power industry is under deregulation. Under this new circumstance, network security analysis is more critical and more difficult. One of the most important issues in network security analysis is voltage stability analysis. Due to the expected higher utilization of equipment induced by competition in a power market that covers bigger power systems, this issue is increasingly acute after deregulation. In this dissertation, some selected topics of voltage stability analysis are covered. In the first part, after a brief review of general concepts of continuation power flow (CPF), investigations on various matrix analysis techniques to improve the speed of CPF calculation for large systems are reported. Based on these improvements, a new CPF algorithm is proposed. This new method is then tested by an inter-area transaction in a large inter-connected power system. In the second part, the Arnoldi algorithm, the best method to find a few minimum singular values for a large sparse matrix, is introduced into the modal analysis for the first time. This new modal analysis is applied to the estimation of the point of voltage collapse and contingency evaluation in voltage security assessment. Simulations show that the new method is very efficient. In the third part, after transient voltage stability component models are investigated systematically, a novel system model for transient voltage stability analysis, which is a logical-algebraic-differential-difference equation (LADDE), is offered. As an example, TCSC (Thyristor controlled series capacitors) is addressed as a transient voltage stabilizing controller. After a TCSC transient voltage stability model is outlined, a new TCSC controller is proposed to enhance both fault related and load increasing related transient voltage stability. Its ability is proven by the simulation.

  19. Ras-mediated deregulation of the circadian clock in cancer.

    PubMed

    Relógio, Angela; Thomas, Philippe; Medina-Pérez, Paula; Reischl, Silke; Bervoets, Sander; Gloc, Ewa; Riemer, Pamela; Mang-Fatehi, Shila; Maier, Bert; Schäfer, Reinhold; Leser, Ulf; Herzel, Hanspeter; Kramer, Achim; Sers, Christine

    2014-01-01

    Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock. PMID:24875049

  20. Deregulated tyrosine-phenylalanine metabolism in pulmonary tuberculosis patients.

    PubMed

    Das, Mrinal Kumar; Bishwal, Subasa Chandra; Das, Aleena; Dabral, Deepti; Badireddy, Vinod Kumar; Pandit, Bhaswati; Varghese, George M; Nanda, Ranjan Kumar

    2015-04-01

    Metabolic profiling of biofluids from tuberculosis (TB) patients would help us in understanding the disease pathophysiology and may also be useful for the development of novel diagnostics and host-directed therapy. In this pilot study we have compared the urine metabolic profiles of two groups of subjects having similar TB symptoms and categorized as active TB (ATB, n = 21) and non-TB (NTB, n = 21) based on GeneXpert test results. Silylation, gas chromatography mass spectrometry, and standard chemometric methods were employed to identify the important molecules and deregulated metabolic pathways. Eleven active TB patients were followed up on longitudinally for comparative urine metabolic profiling with healthy controls (n = 11). A set of 42 features qualified to have a variable importance parameter score of > 1.5 of a partial least-squares discriminate analysis model and fold change of > 1.5 at p value < 0.05 between ATB and NTB. Using these variables, a receiver operating characteristics curve was plotted and the area under the curve was calculated to be 0.85 (95% CI: 0.72-0.96). Several of these variables that represent norepinephrine, gentisic acid, 4-hydroxybenzoic acid, hydroquinone, and 4-hydroxyhippuric acid are part of the tyrosine-phenylalanine metabolic pathway. In the longitudinal study we observed a treatment-dependent trend in the urine metabolome of follow-up samples, and subjects declared as clinically cured showed similar metabolic profile as those of asymptomatic healthy subjects. The deregulated tyrosine-phenylalanine axis reveals a potential target for diagnostics and intervention in TB. PMID:25693719

  1. Deregulated tyrosine-phenylalanine metabolism in pulmonary tuberculosis patients.

    PubMed

    Das, Mrinal Kumar; Bishwal, Subasa Chandra; Das, Aleena; Dabral, Deepti; Badireddy, Vinod Kumar; Pandit, Bhaswati; Varghese, George M; Nanda, Ranjan Kumar

    2015-04-01

    Metabolic profiling of biofluids from tuberculosis (TB) patients would help us in understanding the disease pathophysiology and may also be useful for the development of novel diagnostics and host-directed therapy. In this pilot study we have compared the urine metabolic profiles of two groups of subjects having similar TB symptoms and categorized as active TB (ATB, n = 21) and non-TB (NTB, n = 21) based on GeneXpert test results. Silylation, gas chromatography mass spectrometry, and standard chemometric methods were employed to identify the important molecules and deregulated metabolic pathways. Eleven active TB patients were followed up on longitudinally for comparative urine metabolic profiling with healthy controls (n = 11). A set of 42 features qualified to have a variable importance parameter score of > 1.5 of a partial least-squares discriminate analysis model and fold change of > 1.5 at p value < 0.05 between ATB and NTB. Using these variables, a receiver operating characteristics curve was plotted and the area under the curve was calculated to be 0.85 (95% CI: 0.72-0.96). Several of these variables that represent norepinephrine, gentisic acid, 4-hydroxybenzoic acid, hydroquinone, and 4-hydroxyhippuric acid are part of the tyrosine-phenylalanine metabolic pathway. In the longitudinal study we observed a treatment-dependent trend in the urine metabolome of follow-up samples, and subjects declared as clinically cured showed similar metabolic profile as those of asymptomatic healthy subjects. The deregulated tyrosine-phenylalanine axis reveals a potential target for diagnostics and intervention in TB.

  2. Ras-Mediated Deregulation of the Circadian Clock in Cancer

    PubMed Central

    Relógio, Angela; Thomas, Philippe; Medina-Pérez, Paula; Reischl, Silke; Bervoets, Sander; Gloc, Ewa; Riemer, Pamela; Mang-Fatehi, Shila; Maier, Bert; Schäfer, Reinhold; Leser, Ulf; Herzel, Hanspeter; Kramer, Achim; Sers, Christine

    2014-01-01

    Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock. PMID:24875049

  3. Analysis of Polymorphisms in Genes (AGT, MTHFR, GPIIIa, and GSTP1) Associated with Hypertension, Thrombophilia and Oxidative Stress in Mestizo and Amerindian Populations of México

    PubMed Central

    Juárez-Velázquez, Rocio; Canto, Patricia; Canto-Cetina, Thelma; Rangel-Villalobos, Hector; Rosas-Vargas, Haydee; Rodríguez, Maricela; Canizales-Quinteros, Samuel; Velázquez Wong, Ana Claudia; Ordoñez-Razo, Rosa María; Vilchis-Dorantes, Guadalupe; Coral-Vázquez, Ramón Mauricio

    2010-01-01

    Several polymorphisms related to hypertension, thrombophilia, and oxidative stress has been associated with the development of cardiovascular disease. We analyzed the frequency of M235T angiotensinogen (AGT), A222V 5,10 methylenete-trahydrofolate reductase (MTHFR), L33P glycoprotein IIIa (GPIIIa), and I105V glutathione S-transferase P1 (GSTP1) polymorphisms in 285 individuals belonging to Mexican-Mestizo and five Amerindian population from México, by real time PCR allelic discrimination. Allele and genotype frequencies were compared using χ2 tests. All populations followed the Hardy Weinberg equilibrium for assay markers with the exception of the Triki, whose were in Hardy Weinberg dysequilibrium for the glutathione S-transferase P1 polymorphism. Interestingly, according to all the analyzed single nucleotide polymorphisms (SNPs), the Triki population was the most differentiated and homogeneous group of the six populations analyzed. A comparison of our data with those previously published for some Caucasian, Asian and Black populations showed quite significant differences. These differences were remarkable with all the Mexican populations having a lower frequency of the 105V allele of the glutathione S-transferase P1 and reduced occurrence of the 222A allele of the 5,10 methylenetetrahydrofolate reductase. Our results show the genetic diversity among different Mexican populations and with other racial groups. PMID:20592457

  4. Report of the Task Force on De-Regulation Initiatives.

    ERIC Educational Resources Information Center

    Fishbein, Estelle A.; Blumer, Dennis H.

    In response to a request by the Presidential Task Force on Regulatory Relief, this report offers specific recommendations for reform of federal regulations. A cover letter explains the constraints imposed by the recommended format: that the report is unable to address adequately the area of federal regulatory activity generating the most adverse…

  5. Deregulation of lipid metabolism pathway genes in nasopharyngeal carcinoma cells.

    PubMed

    Daker, Maelinda; Bhuvanendran, Saatheeyavaane; Ahmad, Munirah; Takada, Kenzo; Khoo, Alan Soo-Beng

    2013-03-01

    Nasopharyngeal carcinoma (NPC) is a unique tumour of epithelial origin with a distinct geographical distribution, closely associated with the Epstein‑Barr virus (EBV). EBV‑encoded RNAs (EBERs) are small non‑polyadenylated RNAs that are abundantly expressed in latent EBV‑infected NPC cells. To study the role of EBERs in NPC, we established stable expression of EBERs in HK1, an EBV‑negative NPC cell line. Cells expressing EBERs consistently exhibited an increased growth rate. However, EBERs did not confer resistance towards cisplatin‑induced apoptosis or promote migration or invasion ability in the cells tested. Using microarray gene expression profiling, we identified potential candidate genes that were deregulated in NPC cells expressing EBERs. Gene Ontology analysis of the data set revealed that EBERs upregulate the cellular lipid metabolic process. Upregulation of low‑density lipoprotein receptor (LDLR) and fatty acid synthase (FASN) was observed in EBER‑expressing cells. NPC cells exhibited LDL‑dependent cell proliferation. In addition, a polyphenolic flavonoid compound, quercetin, known to inhibit FASN, was found to inhibit proliferation of NPC cells.

  6. Deregulation of splicing factors and breast cancer development.

    PubMed

    Silipo, Marco; Gautrey, Hannah; Tyson-Capper, Alison

    2015-10-01

    It is well known that many genes implicated in the development and progression of breast cancer undergo aberrant alternative splicing events to produce proteins with pro-cancer properties. These changes in alternative splicing can arise from mutations or single-nucleotide polymorphisms (SNPs) within the DNA sequences of cancer-related genes, which can strongly affect the activity of splicing factors and influence the splice site choice. However, it is important to note that absence of mutations is not sufficient to prevent misleading choices in splice site selection. There is now increasing evidence to demonstrate that the expression profile of ten splicing factors (including SRs and hnRNPs) and eight RNA-binding proteins changes in breast cancer cells compared with normal cells. These modifications strongly influence the alternative splicing pattern of many cancer-related genes despite the absence of any detrimental mutations within their DNA sequences. Thus, a comprehensive assessment of the splicing factor status in breast cancer is important to provide insights into the mechanisms that lead to breast cancer development and metastasis. Whilst most studies focus on mutations that affect alternative splicing in cancer-related genes, this review focuses on splicing factors and RNA-binding proteins that are themselves deregulated in breast cancer and implicated in cancer-related alternative splicing events.

  7. [Deregulation and equity: the Obras Sociales reconversion process in Argentina].

    PubMed

    Findling, Liliana; Arrunada, María; Klimovsky, Ezequiel

    2002-01-01

    The health care services managed by trade unions and known as "Obras Sociales" form the groundwork for Argentina's Social Security and Health system. However, far from taking an equitable approach, these institutions highlight the country's prevailing income disparities, which in turn lead to major differences in access to care. The main focus of this study was the reformulation of social security health policies within the framework of deregulation from 1998 to 2000, analyzing the effects on availability of health care services from an equity perspective. The methodology used two related analytical levels: (1) a macro level viewing the process from the various players' strategies and (2) a micro level featuring the changes within a well-known trade union social security organization during its reconversion process, emphasizing its institutional scope and the opinions of its membership. The results thus pointed to the slow implementation of reforms initiated by the public sector, hindered by constant negotiations among the main corporate actors seeking to serve their particular interests, along with increased inequity and fragmentation due to the limited opening of free choice by members.

  8. MicroRNAs and deregulated gene expression networks in neurodegeneration.

    PubMed

    Sonntag, Kai-Christian

    2010-06-18

    Neurodegeneration is characterized by the progressive loss of neuronal cell types in the nervous system. Although the main cause of cell dysfunction and death in many neurodegenerative diseases is not known, there is increasing evidence that their demise is a result of a combination of genetic and environmental factors which affect key signaling pathways in cell function. This view is supported by recent observations that disease-compromised cells in late-stage neurodegeneration exhibit profound dysregulation of gene expression. MicroRNAs (miRNAs) introduce a novel concept of regulatory control over gene expression and there is increasing evidence that they play a profound role in neuronal cell identity as well as multiple aspects of disease pathogenesis. Here, we review the molecular properties of brain cells derived from patients with neurodegenerative diseases, and discuss how deregulated miRNA/mRNA expression networks could be a mechanism in neurodegeneration. In addition, we emphasize that the dysfunction of these regulatory networks might overlap between different cell systems and suggest that miRNA functions might be common between neurodegeneration and other disease entities.

  9. Power system market implementation in a deregulated environment

    NASA Astrophysics Data System (ADS)

    Silva, Carlos

    2000-10-01

    The opening of the power system markets (also known as deregulation) gives rise to issues never seen before by this industry. One of the most important is the control of information about the cost of generation. Information that used to be common knowledge is now kept private by the new agents of the system (generator companies, distribution companies, etc.). Data such as the generator cost functions are now known only by the owning companies. The result is a new system consisting of a group of independent firms seeking the maximization of their own profit. There have been many proposals to organize the new market in an economically efficient manner. Nevertheless, the uniqueness of the electric power system has prevented the development of such a market. This thesis evaluates the most common proposals using simulations in an auction setting. In addition a new methodology is proposed based on mechanism design, a common technique in economics, that solves some of the practical problems of power system markets (such as the management of limited transmission capacity). In this methodology, when each company acts in its best interest, the outcome is efficient in spite of the information problem cited above. This new methodology, along with the existing methodologies, are tested using simulation and analyzed to create a clear comparison of benefits and disadvantages.

  10. [Deregulation and equity: the Obras Sociales reconversion process in Argentina].

    PubMed

    Findling, Liliana; Arrunada, María; Klimovsky, Ezequiel

    2002-01-01

    The health care services managed by trade unions and known as "Obras Sociales" form the groundwork for Argentina's Social Security and Health system. However, far from taking an equitable approach, these institutions highlight the country's prevailing income disparities, which in turn lead to major differences in access to care. The main focus of this study was the reformulation of social security health policies within the framework of deregulation from 1998 to 2000, analyzing the effects on availability of health care services from an equity perspective. The methodology used two related analytical levels: (1) a macro level viewing the process from the various players' strategies and (2) a micro level featuring the changes within a well-known trade union social security organization during its reconversion process, emphasizing its institutional scope and the opinions of its membership. The results thus pointed to the slow implementation of reforms initiated by the public sector, hindered by constant negotiations among the main corporate actors seeking to serve their particular interests, along with increased inequity and fragmentation due to the limited opening of free choice by members. PMID:12118312

  11. Price-elastic demand in deregulated electricity markets

    SciTech Connect

    Siddiqui, Afzal S.

    2003-05-01

    The degree to which any deregulated market functions efficiently often depends on the ability of market agents to respond quickly to fluctuating conditions. Many restructured electricity markets, however, experience high prices caused by supply shortages and little demand-side response. We examine the implications for market operations when a risk-averse retailer's end-use consumers are allowed to perceive real-time variations in the electricity spot price. Using a market-equilibrium model, we find that price elasticity both increases the retailers revenue risk exposure and decreases the spot price. Since the latter induces the retailer to reduce forward electricity purchases, while the former has the opposite effect, the overall impact of price responsive demand on the relative magnitudes of its risk exposure and end-user price elasticity. Nevertheless, price elasticity decreases cumulative electricity consumption. By extending the analysis to allow for early settlement of demand, we find that forward stage end-user price responsiveness decreases the electricity forward price relative to the case with price-elastic demand only in real time. Moreover, we find that only if forward stage end-user demand is price elastic will the equilibrium electricity forward price be reduced.

  12. How should utilities adjust to the coming deregulated environment?

    SciTech Connect

    Nicewarner, N.A.

    1996-04-01

    A utility`s success in prospering in the changing industry environment will depend on its understanding of the nature and timing of external change. To the extent that a utility can organize its management structure to reflect both regulated and competitive environments, and the role of each in the transition, it should have a good chance at success. The utility environment today is in a remarkable state of structural upheaval. New parties at the table - non-utility developers and large customers - are calling for abandonment of the ancient regulatory compact: sheltered monopoly markets in return for universal utility service and regulated profits. Many customers and the better-prepared competitors are demanding deregulation now. Just as it transformed the airline, long distance telephone and natural gas industries, today`s call for a market-based, largely unregulated power supply industry seems likely to turn the power generation sector, where the bulk of the industry`s investment is found, into a wholly new structure, in which there will be winners and losers-and none of the security of the past.

  13. Effects of the Deregulation on the Concentration of the Brazilian Air Transportation Industry

    NASA Technical Reports Server (NTRS)

    Guterres, Marcelo Xavier; Muller, Carlos

    2003-01-01

    This paper addresses the effects of the deregulation of the Brazilian air transportation industry in terms of the concentration of the market. We will show some metrics that are commonly used to study the concentration of the industry. This paper uses the Herfindhal- Hirschman Index. This index tends to zero in the competitive scenario, with a large number of small firms, and to one in case of a monopolistic scenario. The paper analyses the dynamics of the concentration of the Brazilian domestic air transportation market, in order to evaluate the effects of deregulation. We conclude that the Brazilian market presents oligopoly characteristics and aspects in its current structure that maintain the market concentrated in spite of the Deregulation measures adopted by the aeronautical authority. Keywords: Herfindhal-Hirschman Index, concentration, Deregulation

  14. The effect of deregulation on internal control of agency conflict: Evidence from the electric utility industry

    NASA Astrophysics Data System (ADS)

    Rennie, Craig G.

    I investigate how deregulation leads firms to modify their internal governance structures to help control owner-manager agency conflict. Specifically, I explore how electric utilities respond to wholesale-level deregulation during the ten years surrounding the 1992 Energy Policy Act. I apply factor analysis to observable governance variables that exhibit change among utilities relative to industrial firms, and show that a single common factor captures firms' reliance on internal governance structure to control owner-manager agency problems. I find that deregulating utilities reduce their reliance on internal governance relative to industrial firms. I also show that the negative relation between deregulation and electric utilities' relative reliance on internal governance structure is largely explained by increases in competition and takeover activity among utilities relative to industrial firms. I conclude that competition and takeover activity substitute for firms' relative reliance on internal control of agency conflict.

  15. An assessment of the impact of deregulation on the relative price of electricity in Illinois

    SciTech Connect

    Carlson, J. Lon; Loomis, David

    2008-07-15

    Though it's commonly thought that electricity deregulation has, by and large, failed to deliver its anticipated results, consumers in Illinois have benefited from deregulation when compared to what has happened to rates over the past several years in bordering states. This conclusion is supported by a comparison of nominal and real rates paid by different customer classes, theoretical predictions, and consideration of fuel cost impacts and capacity expansions. (author)

  16. Fuel, environmental, and transmission pricing considerations in a deregulated environment

    NASA Astrophysics Data System (ADS)

    Obessis, Emmanouil Vlassios

    The 1992 National Energy Policy Act drastically changed the traditional structure of the vertically integrated utility. To facilitate increased competition in the power utility sector, all markets related to power generation have been opened to free competition and trading. To survive in the new competitive environment, power producers need to reduce costs and increase efficiency. Fuel marketing strategies are thus, getting more aggressive and fuel markets are becoming more competitive, offering more options regarding fuel supplies and contracts. At the same time, the 1990 Clean Air Act Amendments are taking effect. Although tightening the emission standards, this legislation offers utilities a wider flexibility in choosing compliance strategies. It also set maximum annual allowable levels replacing the traditional uniform maximum emission rates. The bill also introduced the concept of marketable emission allowances and provided for the establishment of nationwide markets where allowances may be traded, sold, or purchased. Several fuel- and emission-constrained algorithms have been historically presented, but those two classes of constraints, in general, were handled independently. The multiobjective optimization model developed in this research work, concurrently satisfies sets of detailed fuel and emission limits, modeling in a more accurate way the fuel supply and environmental limitations and their complexities in the new deregulated operational environment. Development of the implementation software is an integral part of this research project. This software may be useful for both daily scheduling activities and short-term operational planning. A Lagrangian multipliers-based variant is used to solve the problem. Single line searches are used to update the multipliers, thus offering attractive execution times. This work also investigates the applicability of cooperative games to the problem of transmission cost allocation. Interest in game theory as a powerful

  17. Deregulated Renal Calcium and Phosphate Transport during Experimental Kidney Failure.

    PubMed

    Pulskens, Wilco P; Verkaik, Melissa; Sheedfar, Fareeba; van Loon, Ellen P; van de Sluis, Bart; Vervloet, Mark G; Hoenderop, Joost G; Bindels, René J

    2015-01-01

    Impaired mineral homeostasis and inflammation are hallmarks of chronic kidney disease (CKD), yet the underlying mechanisms of electrolyte regulation during CKD are still unclear. Here, we applied two different murine models, partial nephrectomy and adenine-enriched dietary intervention, to induce kidney failure and to investigate the subsequent impact on systemic and local renal factors involved in Ca(2+) and Pi regulation. Our results demonstrated that both experimental models induce features of CKD, as reflected by uremia, and elevated renal neutrophil gelatinase-associated lipocalin (NGAL) expression. In our model kidney failure was associated with polyuria, hypercalcemia and elevated urinary Ca(2+) excretion. In accordance, CKD augmented systemic PTH and affected the FGF23-αklotho-vitamin-D axis by elevating circulatory FGF23 levels and reducing renal αklotho expression. Interestingly, renal FGF23 expression was also induced by inflammatory stimuli directly. Renal expression of Cyp27b1, but not Cyp24a1, and blood levels of 1,25-dihydroxy vitamin D3 were significantly elevated in both models. Furthermore, kidney failure was characterized by enhanced renal expression of the transient receptor potential cation channel subfamily V member 5 (TRPV5), calbindin-D28k, and sodium-dependent Pi transporter type 2b (NaPi2b), whereas the renal expression of sodium-dependent Pi transporter type 2a (NaPi2a) and type 3 (PIT2) were reduced. Together, our data indicates two different models of experimental kidney failure comparably associate with disturbed FGF23-αklotho-vitamin-D signalling and a deregulated electrolyte homeostasis. Moreover, this study identifies local tubular, possibly inflammation- or PTH- and/or FGF23-associated, adaptive mechanisms, impacting on Ca(2+)/Pi homeostasis, hence enabling new opportunities to target electrolyte disturbances that emerge as a consequence of CKD development.

  18. EGFR gene deregulation mechanisms in lung adenocarcinoma: A molecular review.

    PubMed

    Tsiambas, Evangelos; Lefas, Alicia Y; Georgiannos, Stavros N; Ragos, Vasileios; Fotiades, Panagiotis P; Grapsa, Dimitra; Stamatelopoulos, Athanasios; Kavantzas, Nikolaos; Patsouris, Efstratios; Syrigos, Konstantinos

    2016-08-01

    For the last two decades, evolution in molecular biology has expanded our knowledge in decoding a broad spectrum of genomic imbalances that progressively lead normal cells to a neoplastic state and finally to complete malignant transformation. Concerning oncogenes and signaling transduction pathways mediated by them, identification of specific gene alterations remains a critical process for handling patients by applying targeted therapeutic regimens. The epidermal growth factor receptor (EGFR) signaling pathway plays a crucial role in regulating cell proliferation, differentiation and apoptosis in normal cells. EGFR mutations and amplification represent the gene's main deregulation mechanisms in cancers of different histo-genetic origin. Furthermore, intra-cancer molecular heterogeneity due to clonal rise and expansion mainly explains the variable resistance to novel anti-EGFR monoclonal antibody (mAb), and also tyrosine kinase inhibitors (TKIs). According to recently published 2015 WHO new classification, lung cancer is the leading cause of death related to cancer and its incidence is still on the increase worldwide. The majority of patients suffering from lung cancer are diagnosed with epithelial tumors (adenocarcinoma predominantly and squamous cell carcinoma represent ∼85% of all pathologically defined lung cancer cases). In those patients, EGFR-activating somatic mutations in exons 18/19/20/21 modify patients' sensitivity (i.e. exon 21 L858R, exon 19 LREA deletion) or resistance (ie exon 20 T790M and/or insertion) to TKI mediated targeted therapeutic strategies. Additionally, the role of specific micro-RNAs that affect EGFR regulation is under investigation. In the current review, we focused on EGFR gene/protein structural and functional aspects and the corresponding alterations that occur mainly in lung adenocarcinoma to critically modify its molecular landscape. PMID:27461822

  19. Oral cancer: Deregulated molecular events and their use as biomarkers.

    PubMed

    Sinevici, Nicoleta; O'sullivan, Jeff

    2016-10-01

    Oral Cancer (OC) is a subset of head and neck cancer (HNC) with an annual worldwide incidence of 275,000 cases. OC remains a significant burden worldwide in terms of diagnosis, treatment and prognosis. Despite desirable outcomes in early diagnosed OCs and treatment advances most OCs are detected in advanced stages. The 5-year survival rate of early-stage disease is ∼80% and that of late-stage disease is only ∼20%. Recurrence and chemoresistance from a treatment point of view and pain and disfiguration are important factors contributing to the high morbidity and mortality of OC. Furthermore the process of oral carcinogenesis is complex and not yet fully understood. Consequently numerous potential biomarkers have been hypothesised though controversial results across the board hamper their clinical implementation. Of greatest advantage would be biomarkers signalling early events preceeding OC. Biomarker targets predominately involve deregulated molecular events that participate in cell signalling, growth, survival, motility, angiogenesis and cell cycle control but can also use changes in metabolic genes to discriminate healthy form disease state. Promising potential biomarkers include the growth signalling oncogenes, Epidermal Growth Factor Receptor and Cyclin D1, the anti-growth signalling components p53 and p21, apoptotic effectors such as Bcl-2 and also components involved in immortalisation, angiogenesis, invasion and metastasis processes. Translation of these potential biomakers to the patients is closer than ever though few issues remain to be resolved. Firstly large clinical trials are needed to validate their clinical applicability but also standardised methods of collection, storage and processing methods are needed to minimise variability. PMID:27688099

  20. MYC Deregulation in Gastric Cancer and Its Clinicopathological Implications

    PubMed Central

    de Souza, Carolina Rosal Teixeira; Leal, Mariana Ferreira; Calcagno, Danielle Queiroz; Costa Sozinho, Eliana Kelly; Borges, Bárbara do Nascimento; Montenegro, Raquel Carvalho; dos Santos, Ândrea Kely Campos Ribeiro; dos Santos, Sidney Emanuel Batista; Ribeiro, Helem Ferreira; Assumpção, Paulo Pimentel; de Arruda Cardoso Smith, Marília; Burbano, Rommel Rodríguez

    2013-01-01

    Our study investigated the relationship between MYC alterations and clinicopathological features in gastric cancers. We evaluated the effect of MYC mRNA expression and its protein immunoreactivity, as well as copy number variation, promoter DNA methylation, and point mutations, in 125 gastric adenocarcinoma and 67 paried non-neoplastic tissues. We observed that 77% of the tumors presented MYC immunoreactivity which was significantly associated with increased mRNA expression (p<0.05). These observations were associated with deeper tumor extension and the presence of metastasis (p<0.05). MYC protein expression was also more frequently observed in intestinal-type than in diffuse-type tumors (p<0.001). Additionally, MYC mRNA and protein expression were significantly associated with its copy number (p<0.05). The gain of MYC copies was associated with late-onset, intestinal-type, advanced tumor stage, and the presence of distant metastasis (p<0.05). A hypomethylated MYC promoter was detected in 86.4% of tumor samples. MYC hypomethylation was associated with diffuse-type, advanced tumor stage, deeper tumor extension, and the presence of lymph node metastasis (p<0.05). Moreover, eighteen tumor samples presented at least one known mutation. The presence of MYC mutations was associated with diffuse-type tumor (p<0.001). Our results showed that MYC deregulation was mainly associated with poor prognostic features and also reinforced the presence of different pathways involved in intestinal-type and diffuse-type gastric carcinogenesis. Thus, our findings suggest that MYC may be a useful marker for clinical stratification and prognosis. PMID:23717612

  1. Deregulated Fcγ receptor expression in patients with CIDP

    PubMed Central

    Quast, Isaak; Cueni, Flavio; Nimmerjahn, Falk; Tackenberg, Björn

    2015-01-01

    Objective: To evaluate the expression of activating and inhibitory Fc-gamma receptors (FcγRs) before and during clinically effective therapy with IV immunoglobulin (IVIg) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: Peripheral blood leukocyte subsets, including classical CD14highCD16− and nonclassical inflammatory CD14lowCD16+ monocytes as well as naive CD19+CD27− and memory CD19+CD27+ B cells, were obtained at baseline and monitored at 2 and 4–8 weeks after initiation of IVIg therapy. Results: Compared with healthy donors matched by age and sex, patients with CIDP showed increased expression levels of the activating high-affinity FcγR1 on CD14highCD16− (p < 0.001) and CD14lowCD16+ monocytes (p < 0.001). Expression of the activating low-affinity FcγRIIA was increased on CD14lowCD16+ monocytes (p = 0.023). Conversely, expression of the inhibitory FcγRIIB was reduced on naive (p = 0.009) and memory (p = 0.002) B cells as well as on CD14highCD16− monocytes (p = 0.046). Clinically effective IVIg therapy partially restored deregulated FcγR expression on B cell subsets and monocytes. Conclusions: The FcγR regulatory system is disturbed in patients with CIDP. Balancing activating vs inhibitory FcγR expression might provide a clinical benefit for patients with CIDP. PMID:26380354

  2. Federal Agencies

    ERIC Educational Resources Information Center

    Kyle, George M.

    1976-01-01

    The status of two of life's necessities, air and water, is of crucial importance to the future of American parks and recreation programs, and continued cooperation among federal, state, local and private sectors is necessary to preserve them. (JD)

  3. Posttranscriptional deregulation of signaling pathways in meningioma subtypes by differential expression of miRNAs

    PubMed Central

    Ludwig, Nicole; Kim, Yoo-Jin; Mueller, Sabine C.; Backes, Christina; Werner, Tamara V.; Galata, Valentina; Sartorius, Elke; Bohle, Rainer M.; Keller, Andreas; Meese, Eckart

    2015-01-01

    Background Micro (mi)RNAs are key regulators of gene expression and offer themselves as biomarkers for cancer development and progression. Meningioma is one of the most frequent primary intracranial tumors. As of yet, there are limited data on the role of miRNAs in meningioma of different histological subtypes and the affected signaling pathways. Methods In this study, we compared expression of 1205 miRNAs in different meningioma grades and histological subtypes using microarrays and independently validated deregulation of selected miRNAs with quantitative real-time PCR. Clinical utility of a subset of miRNAs as biomarkers for World Health Organization (WHO) grade II meningioma based on quantitative real-time data was tested. Potential targets of deregulated miRNAs were discovered with an in silico analysis. Results We identified 13 miRNAs deregulated between different subtypes of benign meningiomas, and 52 miRNAs deregulated in anaplastic meningioma compared with benign meningiomas. Known and putative target genes of deregulated miRNAs include genes involved in epithelial-to-mesenchymal transition for benign meningiomas, and Wnt, transforming growth factor–β, and vascular endothelial growth factor signaling for higher-grade meningiomas. Furthermore, a 4-miRNA signature (miR-222, -34a*, -136, and -497) shows promise as a biomarker differentiating WHO grade II from grade I meningiomas with an area under the curve of 0.75. Conclusions Our data provide novel insights into the contribution of miRNAs to the phenotypic spectrum in benign meningiomas. By deregulating translation of genes belonging to signaling pathways known to be important for meningioma genesis and progression, miRNAs provide a second in line amplification of growth promoting cellular signals. MiRNAs as biomarkers for diagnosis of aggressive meningiomas might prove useful and should be explored further in a prospective manner. PMID:25681310

  4. Review of MicroRNA Deregulation in Oral Cancer. Part I

    PubMed Central

    Miloro, Michael; Zhou, Xiaofeng

    2011-01-01

    ABSTRACT Objectives Oral cancer is the sixth most common malignancy worldwide. Cancer development and progression requires inactivation of tumour suppressor genes and activation of proto-oncogenes. Expression of these genes is in part dependant on RNA and microRNA based mechanisms. MicroRNAs are essential regulators of diverse cellular processes including proliferation, differentiation, apoptosis, survival, motility, invasion and morphogenesis. Several microRNAs have been found to be aberrantly expressed in various cancers including oral cancer. The purpose of this article was to review the literature related to microRNA deregulation in the head and neck/oral cavity cancers. Material and Methods A comprehensive review of the available literature from 2000 to 2011 relevant to microRNA deregulation in oral cancer was undertaken using PubMed, Medline, Scholar Google and Scopus. Keywords for the search were: microRNA and oral cancer, microRNA and squamous cell carcinoma, microRNA deregulation. Only full length articles in the English language were included. Strengths and limitations of each study are presented in this review. Results Several studies were identified that investigated microRNA alternations in the head and neck/oral cavity cancers. Significant progress has been made in identification of microRNA deregulation in these cancers. It has been evident that several microRNAs were found to be deregulated specifically in oral cavity cancers. Among these, several microRNAs have been functionally validated and their potential target genes have been identified. Conclusions These findings on microRNA deregulation in cancer further enhance our understanding of the disease progression, response to treatment and may assist with future development of targeted therapy. PMID:24421988

  5. Optimal CBM of Tie Lines between Control Areas under Deregulated Environment

    NASA Astrophysics Data System (ADS)

    Kuraishi, Hideaki; Yokoyama, Akihiko

    In order to keep power supply reliability at a certain level, electric power utilities have a certain amount of reserved capacity. When no generator outage or no unexpected large power demand occurs, however, the reserved capacity is regarded as surplus facility. To reduce the reserved capacity, some margin is reserved in tie lines between utilities. This margin is called Capacity Benefit Margin (CBM). In this study, a method of calculating optimal CBM in tie line under deregulated environment is described and two kind of optimal CBM are proposed. As a result, it is shown how the deregulation affects the optimal CBM by using numerical simulation for IEE Japan West 30 test system.

  6. Exts and the AGT Relations

    NASA Astrophysics Data System (ADS)

    Neguţ, Andrei

    2016-09-01

    We prove the connection between the Nekrasov partition function of {N=2} super-symmetric U(2) gauge theory with adjoint matter and conformal blocks for the Virasoro algebra, as predicted by the Alday-Gaiotto-Tachikawa relations. Mathematically, this is achieved by relating the Carlsson-Okounkov Ext vector bundle on the moduli space of rank 2 sheaves with Liouville vertex operators. Our approach is geometric in nature, and uses a new method for intersection-theoretic computations of the Ext operator.

  7. AGT-102 automotive gas turbine

    NASA Technical Reports Server (NTRS)

    1981-01-01

    Development of a gas turbine powertrain with a 30% fuel economy improvement over a comparable S1 reciprocating engine, operation within 0.41 HC, 3.4 CO, and 0.40 NOx grams per mile emissions levels, and ability to use a variety of alternate fuels is summarized. The powertrain concept consists of a single-shaft engine with a ceramic inner shell for containment of hot gasses and support of twin regenerators. It uses a fixed-geometry, lean, premixed, prevaporized combustor, and a ceramic radial turbine rotor supported by an air-lubricated journal bearing. The engine is coupled to the vehicle through a widerange continuously variable transmission, which utilizes gearing and a variable-ratio metal compression belt. A response assist flywheel is used to achieve acceptable levels of engine response. The package offers a 100 lb weight advantage in a Chrysler K Car front-wheel-drive installation. Initial layout studies, preliminary transient thermal analysis, ceramic inner housing structural analysis, and detailed performance analysis were carried out for the basic engine.

  8. Systematic Analysis Reveals that Cancer Mutations Converge on Deregulated Metabolism of Arachidonate and Xenobiotics.

    PubMed

    Gatto, Francesco; Schulze, Almut; Nielsen, Jens

    2016-07-19

    Mutations are the basis of the clonal evolution of most cancers. Nevertheless, a systematic analysis of whether mutations are selected in cancer because they lead to the deregulation of specific biological processes independent of the type of cancer is still lacking. In this study, we correlated the genome and transcriptome of 1,082 tumors. We found that nine commonly mutated genes correlated with substantial changes in gene expression, which primarily converged on metabolism. Further network analyses circumscribed the convergence to a network of reactions, termed AraX, that involves the glutathione- and oxygen-mediated metabolism of arachidonic acid and xenobiotics. In an independent cohort of 4,462 samples, all nine mutated genes were consistently correlated with the deregulation of AraX. Among all of the metabolic pathways, AraX deregulation represented the strongest predictor of patient survival. These findings suggest that oncogenic mutations drive a selection process that converges on the deregulation of the AraX network. PMID:27396332

  9. The Italian Middle School in a Deregulation Era: Modernity through Path-Dependency and Global Models

    ERIC Educational Resources Information Center

    Mincu, Monica E.

    2015-01-01

    In the current context of intensified moves towards educational deregulation, the configuration of the Italian middle school and its relationship to education governance is an interesting case. Historically, it represents a unique example of the successful "decision-making" model of the welfarist era. Despite some internal constraints,…

  10. Electric Deregulation: Don't Get the Cart before the Horse.

    ERIC Educational Resources Information Center

    Schaeffer, Statton C.

    1999-01-01

    Examines the development of a campus energy-monitoring system and three energy strategies to help control energy costs in a deregulated environment. Strategies discussed involve purchasing off-campus electric energy, modifying power-plant technology, and considering third-party ownership of the power plant. (GR)

  11. Internationalization, Deregulation and the Expansion of Higher Education in Korea: An Historical Overview

    ERIC Educational Resources Information Center

    Green, Christopher

    2015-01-01

    The purpose of this article is to provide an overview of internationalization policies in Korean higher education since 1993. Deregulation was a key strategy of Korean governments, but this strategy has led to an increasing oversupply of enrolment capacity. In response, the current government is implementing a system of reregulation to reduce the…

  12. Short-Term Effects of State Deregulation on the Adequacy and Equity of School Facility Projects.

    ERIC Educational Resources Information Center

    Kowalski, Theodore J.; Decman, John C.

    2002-01-01

    In 1995, the Indiana Legislature deregulated state controls over public-school construction projects by reducing the status of required specifications to guidelines. Also, local taxpayers were given greater authority to prevent proposed projects. This study examines the short-term effects of this policy shift. (Contains 5 tables and 16…

  13. Competitive pricing of nonrenewable natural resources: cases of increasing costs and of deregulation under uncertainty

    SciTech Connect

    Drury, R.C.

    1982-01-01

    This thesis examines the time path of the competitive price for exhaustible natural resources when the current extraction costs increase through time due to the effects of past extraction. The analysis is done within a partial-equilibrium framework. The situation of increasing costs will occur whenever the material differs in its extraction costs and there is choice as to the order in which the material is removed. This thesis also examines the behavior of an exhaustible natural resource sector that is currently under price regulation but where the industry may be deregulated. The knowledge about the possible deregulation date is contained in a general subjective density function which has a continuum of possible dates and their likelihood of being the date of deregulation. The effects on the competitive time paths in a world of certainty of different dates for the removal of price ceilings and price floors are also examined. And there is an examination of the special case where the uncertainty is described by a negative exponential distribution. All the results about regulation and deregulation differ immensely from those of a static analysis.

  14. The critical protein interactions and structures that elicit growth deregulation in cancer and viral replication.

    PubMed

    Ou, Horng D; May, Andrew P; O'Shea, Clodagh C

    2011-01-01

    One of the greatest challenges in biomedicine is to define the critical targets and network interactions that are subverted to elicit growth deregulation in human cells. Understanding and developing rational treatments for cancer requires a definition of the key molecular targets and how they interact to elicit the complex growth deregulation phenotype. Viral proteins provide discerning and powerful probes to understand both how cells work and how they can be manipulated using a minimal number of components. The small DNA viruses have evolved to target inherent weaknesses in cellular protein interaction networks to hijack the cellular DNA and protein replication machinery. In the battle to escape the inevitability of senescence and programmed cell death, cancers have converged on similar mechanisms, through the acquisition and selection of somatic mutations that drive unchecked cellular replication in tumors. Understanding the dynamic mechanisms through which a minimal number of viral proteins promote host cells to undergo unscheduled and pathological replication is a powerful strategy to identify critical targets that are also disrupted in cancer. Viruses can therefore be used as tools to probe the system-wide protein-protein interactions and structures that drive growth deregulation in human cells. Ultimately this can provide a path for developing system context-dependent therapeutics. This review will describe ongoing experimental approaches using viruses to study pathways deregulated in cancer, with a particular focus on viral cellular protein-protein interactions and structures. PMID:21061422

  15. Internationalization, Deregulation and the Extension of Higher Education in Korea: A Further Note

    ERIC Educational Resources Information Center

    Jin, Jang C.

    2015-01-01

    The Korean government implemented several educational policies to enhance internationalization of higher education such as deregulation of higher education, classroom instructions in English, and faculty publications in international refereed journals. However, the speed of globalization has been lagging behind (Green, 2015). Alternatively, this…

  16. Federated Giovanni

    NASA Technical Reports Server (NTRS)

    Lynnes, C.

    2014-01-01

    Federated Giovanni is a NASA-funded ACCESS project to extend the scope of the GES DISC Giovanni online analysis tool to 4 other Distributed Active Archive Centers within EOSDIS: OBPG, LP-DAAC, MODAPS and PO.DAAC. As such, it represents a significant instance of sharing technology across the DAACs. We also touch on several sub-areas that are also sharable, such as Giovanni URLs, workflows and OGC-accessible services.

  17. The Unilateral, Self-Deregulation of AT&T

    NASA Astrophysics Data System (ADS)

    Maloff, Joel H.

    1990-01-01

    The provision of telecommunications products and services in the United States has been dominated by AT&T and the Bell System for more than one hundred years. From the early days of telephones, it was clear that some framework of logic was required to provide "universal" telephone services to the vast majority of American citizens. The concept was known as "natural monopoly", and for the most part, has served us well. We are all aware of statements concerning absolute power corrupting absolutely, and AT&T has not been immune to this law of human nature. Several times during the past century, action has been required by the Federal Government to regulate and constrain AT&T and the Bell System from anti-competitive and predatory actions. These have been called consent decrees, Computer Inquiry II, Computer Inquiry III, and the Modified Final Judgment. The regulations and constraints imposed upon AT&T, with good reason, are now becoming eroded. The perception of a more highly competitive marketplace capable of accommodating an unrestrained AT&T, the impact of uncoordinated national and regional government policies, and unilateral actions by AT&T themselves are bringing us to the edge of an abyss. There are substantial reasons to believe that AT&T will use its considerable might to eliminate its competitors, once free to do so. Must we be doomed to repeat history with still another antitrust case against AT&T some years from now? Logic demands that we learn from the past, and that telecommunications policies be based upon that knowledge.

  18. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia.

    PubMed

    Gröschel, Stefan; Sanders, Mathijs A; Hoogenboezem, Remco; de Wit, Elzo; Bouwman, Britta A M; Erpelinck, Claudia; van der Velden, Vincent H J; Havermans, Marije; Avellino, Roberto; van Lom, Kirsten; Rombouts, Elwin J; van Duin, Mark; Döhner, Konstanze; Beverloo, H Berna; Bradner, James E; Döhner, Hartmut; Löwenberg, Bob; Valk, Peter J M; Bindels, Eric M J; de Laat, Wouter; Delwel, Ruud

    2014-04-10

    Chromosomal rearrangements without gene fusions have been implicated in leukemogenesis by causing deregulation of proto-oncogenes via relocation of cryptic regulatory DNA elements. AML with inv(3)/t(3;3) is associated with aberrant expression of the stem-cell regulator EVI1. Applying functional genomics and genome-engineering, we demonstrate that both 3q rearrangements reposition a distal GATA2 enhancer to ectopically activate EVI1 and simultaneously confer GATA2 functional haploinsufficiency, previously identified as the cause of sporadic familial AML/MDS and MonoMac/Emberger syndromes. Genomic excision of the ectopic enhancer restored EVI1 silencing and led to growth inhibition and differentiation of AML cells, which could be replicated by pharmacologic BET inhibition. Our data show that structural rearrangements involving the chromosomal repositioning of a single enhancer can cause deregulation of two unrelated distal genes, with cancer as the outcome.

  19. Decoding Parkinson’s Disease Pathogenesis: The Role of Deregulated mRNA Translation

    PubMed Central

    Martin, Ian

    2016-01-01

    Mutations in a number of genes cause rare familial forms of Parkinson’s disease and provide profound insight into potential mechanisms governing disease pathogenesis. Recently, a role for translation and metabolism of mRNA has emerged in the development of various neurodegenerative disorders including Parkinson’s disease (PD). In PD, preliminary evidence supports a role for aberrant translation in the disease process stemming from mutations in several genes. Translation control is central to maintaining organism homeostasis under variable environmental conditions and deregulation of this may predispose to certain stressors. Hypothetically, deregulated translation may be detrimental to neuronal viability in PD through the misexpression of a subset of transcripts or through the impact of excessive bulk translation on energy consumption and burden on protein homeostatic mechanisms. While compelling preliminary evidence exists to support a role for translation in PD, much more work is required to identify specific mechanisms linking altered translation to the disease process. PMID:26889638

  20. Application of games with incomplete information for pricing electricity in deregulated power pools

    SciTech Connect

    Ferrero, R.W.; Rivera, J.F.; Shahidehpour, S.M.

    1998-02-01

    The authors present a game theoretical approach to the problem of pricing electricity in deregulated energy marketplaces. They assume that an Independent System Operator receives bids by Pool participants and defines transactions among participants by looking for the minimum price that satisfies the demand in the Pool. The competition among Pool participants is modeled as a non-cooperative game with incomplete information. They assume that each Pool participant knows its own operation costs but does not know his opponents` operation costs. The game with incomplete information is transformed into a game with complete, but imperfect, information and solved using the Nash equilibrium idea. The approach presented in this paper is geared towards providing support for pricing electricity in deregulated Pools.

  1. Psychology of change: Models and implications for nuclear plants in an era of deregulation

    SciTech Connect

    Gates, W.G.; Stark, J.A.

    1999-09-01

    This presentation explores the psychology of change in the implications that it has for nuclear plants during this era of deregulation. The authors analyze models that work, models that have failed in the past, and specific findings and applications based on 2 yr of research, as well as the results regarding the impact of the psychology of change on the Fort Calhoun nuclear station in Nebraska.

  2. Identification of Long Non-Coding RNAs Deregulated in Multiple Myeloma Cells Resistant to Proteasome Inhibitors

    PubMed Central

    Malek, Ehsan; Kim, Byung-Gyu; Driscoll, James J.

    2016-01-01

    While the clinical benefit of proteasome inhibitors (PIs) for multiple myeloma (MM) treatment remains unchallenged, dose-limiting toxicities and the inevitable emergence of drug resistance limit their long-term utility. Disease eradication is compromised by drug resistance that is either present de novo or therapy-induced, which accounts for the majority of tumor relapses and MM-related deaths. Non-coding RNAs (ncRNAs) are a broad class of RNA molecules, including long non-coding RNAs (lncRNAs), that do not encode proteins but play a major role in regulating the fundamental cellular processes that control cancer initiation, metastasis, and therapeutic resistance. While lncRNAs have recently attracted significant attention as therapeutic targets to potentially improve cancer treatment, identification of lncRNAs that are deregulated in cells resistant to PIs has not been previously addressed. We have modeled drug resistance by generating three MM cell lines with acquired resistance to either bortezomib, carfilzomib, or ixazomib. Genome-wide profiling identified lncRNAs that were significantly deregulated in all three PI-resistant cell lines relative to the drug-sensitive parental cell line. Strikingly, certain lncRNAs deregulated in the three PI-resistant cell lines were also deregulated in MM plasma cells isolated from newly diagnosed patients compared to healthy plasma cells. Taken together, these preliminary studies strongly suggest that lncRNAs represent potential therapeutic targets to prevent or overcome drug resistance. More investigations are ongoing to expand these initial studies in a greater number of MM patients to better define lncRNAs signatures that contribute to PI resistance in MM. PMID:27782060

  3. Multi-objective Decision Based Available Transfer Capability in Deregulated Power System Using Heuristic Approaches

    NASA Astrophysics Data System (ADS)

    Pasam, Gopi Krishna; Manohar, T. Gowri

    2015-07-01

    Determination of available transfer capability (ATC) requires the use of experience, intuition and exact judgment in order to meet several significant aspects in the deregulated environment. Based on these points, this paper proposes two heuristic approaches to compute ATC. The first proposed heuristic algorithm integrates the five methods known as continuation repeated power flow, repeated optimal power flow, radial basis function neural network, back propagation neural network and adaptive neuro fuzzy inference system to obtain ATC. The second proposed heuristic model is used to obtain multiple ATC values. Out of these, a specific ATC value will be selected based on a number of social, economic, deregulated environmental constraints and related to specific applications like optimization, on-line monitoring, and ATC forecasting known as multi-objective decision based optimal ATC. The validity of results obtained through these proposed methods are scrupulously verified on various buses of the IEEE 24-bus reliable test system. The results presented and derived conclusions in this paper are very useful for planning, operation, maintaining of reliable power in any power system and its monitoring in an on-line environment of deregulated power system. In this way, the proposed heuristic methods would contribute the best possible approach to assess multiple objective ATC using integrated methods.

  4. Exploration of Deregulated Long Non-Coding RNAs in Association with Hepatocarcinogenesis and Survival.

    PubMed

    Shen, Jing; Siegel, Abby B; Remotti, Helen; Wang, Qiao; Shen, Yueyue; Santella, Regina M

    2015-09-10

    Long non-coding RNAs (lncRNAs) are larger than 200 nucleotides in length and pervasively expressed across the genome. An increasing number of studies indicate that lncRNA transcripts play integral regulatory roles in cellular growth, division, differentiation and apoptosis. Deregulated lncRNAs have been observed in a variety of human cancers, including hepatocellular carcinoma (HCC). We determined the expression profiles of 90 lncRNAs for 65 paired HCC tumor and adjacent non-tumor tissues, and 55 lncRNAs were expressed in over 90% of samples. Eight lncRNAs were significantly down-regulated in HCC tumor compared to non-tumor tissues (p < 0.05), but no lncRNA achieved statistical significance after Bonferroni correction for multiple comparisons. Within tumor tissues, carrying more aberrant lncRNAs (6-7) was associated with a borderline significant reduction Cancers 2015, 7 1848 in survival (HR = 8.5, 95% CI: 1.0-72.5). The predictive accuracy depicted by the AUC was 0.93 for HCC survival when using seven deregulated lncRNAs (likelihood ratio test p = 0.001), which was similar to that combining the seven lncRNAs with tumor size and treatment (AUC = 0.96, sensitivity = 87%, specificity = 87%). These data suggest the potential association of deregulated lncRNAs with hepatocarcinogenesis and HCC survival.

  5. Multi-objective Decision Based Available Transfer Capability in Deregulated Power System Using Heuristic Approaches

    NASA Astrophysics Data System (ADS)

    Pasam, Gopi Krishna; Manohar, T. Gowri

    2016-09-01

    Determination of available transfer capability (ATC) requires the use of experience, intuition and exact judgment in order to meet several significant aspects in the deregulated environment. Based on these points, this paper proposes two heuristic approaches to compute ATC. The first proposed heuristic algorithm integrates the five methods known as continuation repeated power flow, repeated optimal power flow, radial basis function neural network, back propagation neural network and adaptive neuro fuzzy inference system to obtain ATC. The second proposed heuristic model is used to obtain multiple ATC values. Out of these, a specific ATC value will be selected based on a number of social, economic, deregulated environmental constraints and related to specific applications like optimization, on-line monitoring, and ATC forecasting known as multi-objective decision based optimal ATC. The validity of results obtained through these proposed methods are scrupulously verified on various buses of the IEEE 24-bus reliable test system. The results presented and derived conclusions in this paper are very useful for planning, operation, maintaining of reliable power in any power system and its monitoring in an on-line environment of deregulated power system. In this way, the proposed heuristic methods would contribute the best possible approach to assess multiple objective ATC using integrated methods.

  6. The impact of a deregulated European electricity market on Volvo in Sweden

    SciTech Connect

    Dag, S.

    1998-07-01

    The member countries within the European Union (EU) have agreed to open all national electricity markets for competition, starting January 1, 1999. The electricity market in Sweden is deregulated since January 1, 1996. The deregulation of the electricity markets will gradually shift the electricity price levels in different countries towards an equal price level, which will most likely be close to the levels on the Continental Europe. A deregulated European electricity market may change the competition situation for Swedish industries dramatically. The capacity in electric generation with low operating costs in Sweden has led to very low electricity prices and high usage level compared to other EU countries. The consumption level of electric energy per capita is nearly three times higher in Sweden than the average per capita EU usage. The high level of electricity consumption is typical also of industrial customers in Sweden. Studies of Volvo Car Corporation have shown that the Volvo car plant in Torslanda, Sweden utilizes substantially more electric energy per manufactured car than the Volvo car plant in Gent, Belgium. A method is developed to transform the Torslanda plant from a low energy efficiency state to a higher energy efficiency state by modeling. The method is based on the Life Cycle Cost (LCC) concept and includes optimization models of the two plants with mixed integer linear programming (MILP).

  7. Technology transfer: trends in the federalization of biomedical research.

    PubMed

    Bulleit, T N; Bonnet, S M

    1996-07-01

    Federal involvement in biomedical research has increased significantly in the postwar era, particularly throughout the 1980s and early 1990s. New federal laws and regulations now offer unprecedented opportunities to commercialize federally funded and conducted research, essentially creating a new field of "technology transfer" law. As a result, the biomedical research sector of the health care industry must master a number of relatively new and still developing federal laws, regulations, policies, and concerns that will probably continue to significantly affect its operations. To assist academic medical centers and others in understanding the federal presence in biomedical research, the authors give a short history of technology transfer laws and issues and summarize some of the current main areas of federal interest, including federal oversight of federally funded research, sponsored research agreements, conflict of interest, scientific misconduct, and the prospect of government price control over some biomedical inventions. The authors caution academic medical centers to realize that recent trends favoring deregulation and budget cutting could diminish federal involvement in the future. Thus, research institutions should keep abreast not only of existing rules and policies but of ongoing legislative and regulatory activities that portend possible changes.

  8. Technology transfer: trends in the federalization of biomedical research.

    PubMed

    Bulleit, T N; Bonnet, S M

    1996-07-01

    Federal involvement in biomedical research has increased significantly in the postwar era, particularly throughout the 1980s and early 1990s. New federal laws and regulations now offer unprecedented opportunities to commercialize federally funded and conducted research, essentially creating a new field of "technology transfer" law. As a result, the biomedical research sector of the health care industry must master a number of relatively new and still developing federal laws, regulations, policies, and concerns that will probably continue to significantly affect its operations. To assist academic medical centers and others in understanding the federal presence in biomedical research, the authors give a short history of technology transfer laws and issues and summarize some of the current main areas of federal interest, including federal oversight of federally funded research, sponsored research agreements, conflict of interest, scientific misconduct, and the prospect of government price control over some biomedical inventions. The authors caution academic medical centers to realize that recent trends favoring deregulation and budget cutting could diminish federal involvement in the future. Thus, research institutions should keep abreast not only of existing rules and policies but of ongoing legislative and regulatory activities that portend possible changes. PMID:9158337

  9. Deregulation of the Building Code and the Norwegian Approach to Regulation of Accessibility in the Built Environment.

    PubMed

    Lyngstad, Pål

    2016-01-01

    Deregulation is on the political agenda in the European countries. The Norwegian building code related to universal design and accessibility is challenged. To meet this, the Norwegian Building Authority have chosen to examine established truths and are basing their revised code on scientific research and field tests. But will this knowledge-based deregulation comply within the framework of the anti-discrimination act and, and if not: who suffers and to what extent? PMID:27534290

  10. Deregulation of purine pathway in Bacillus subtilis and its use in riboflavin biosynthesis

    PubMed Central

    2014-01-01

    Background Purine nucleotides are essential metabolites for living organisms because they are involved in many important processes, such as nucleic acid synthesis, energy supply, and biosynthesis of several amino acids and riboflavin. Owing to the pivotal roles of purines in cell physiology, the pool of intracellular purine nucleotides must be maintained under strict control, and hence the de novo purine biosynthetic pathway is tightly regulated by transcription repression and inhibition mechanism. Deregulation of purine pathway is essential for this pathway engineering in Bacillus subtilis. Results Deregulation of purine pathway was attempted to improve purine nucleotides supply, based on a riboflavin producer B. subtilis strain with modification of its rib operon. To eliminate transcription repression, the pur operon repressor PurR and the 5’-UTR of pur operon containing a guanine-sensing riboswitch were disrupted. Quantitative RT-PCR analysis revealed that the relative transcription levels of purine genes were up-regulated about 380 times. Furthermore, site-directed mutagenesis was successfully introduced into PRPP amidotransferase (encoded by purF) to remove feedback inhibition by homologous alignment and analysis. Overexpression of the novel mutant PurF (D293V, K316Q and S400W) significantly increased PRPP amidotransferase activity and triggered a strong refractory effect on purine nucleotides mediated inhibition. Intracellular metabolite target analysis indicated that the purine nucleotides supply in engineered strains was facilitated by a stepwise gene-targeted deregulation. With these genetic manipulations, we managed to enhance the metabolic flow through purine pathway and consequently increased riboflavin production 3-fold (826.52 mg/L) in the purF-VQW mutant strain. Conclusions A sequential optimization strategy was applied to deregulate the rib operon and purine pathway of B. subtilis to create genetic diversities and to improve riboflavin production

  11. Multi-Objective Differential Evolution for Voltage Security Constrained Optimal Power Flow in Deregulated Power Systems

    NASA Astrophysics Data System (ADS)

    Roselyn, J. Preetha; Devaraj, D.; Dash, Subhransu Sekhar

    2013-11-01

    Voltage stability is an important issue in the planning and operation of deregulated power systems. The voltage stability problems is a most challenging one for the system operators in deregulated power systems because of the intense use of transmission line capabilities and poor regulation in market environment. This article addresses the congestion management problem avoiding offline transmission capacity limits related to voltage stability by considering Voltage Security Constrained Optimal Power Flow (VSCOPF) problem in deregulated environment. This article presents the application of Multi Objective Differential Evolution (MODE) algorithm to solve the VSCOPF problem in new competitive power systems. The maximum of L-index of the load buses is taken as the indicator of voltage stability and is incorporated in the Optimal Power Flow (OPF) problem. The proposed method in hybrid power market which also gives solutions to voltage stability problems by considering the generation rescheduling cost and load shedding cost which relieves the congestion problem in deregulated environment. The buses for load shedding are selected based on the minimum eigen value of Jacobian with respect to the load shed. In the proposed approach, real power settings of generators in base case and contingency cases, generator bus voltage magnitudes, real and reactive power demands of selected load buses using sensitivity analysis are taken as the control variables and are represented as the combination of floating point numbers and integers. DE/randSF/1/bin strategy scheme of differential evolution with self-tuned parameter which employs binomial crossover and difference vector based mutation is used for the VSCOPF problem. A fuzzy based mechanism is employed to get the best compromise solution from the pareto front to aid the decision maker. The proposed VSCOPF planning model is implemented on IEEE 30-bus system, IEEE 57 bus practical system and IEEE 118 bus system. The pareto optimal

  12. Understanding the Federal Courts.

    ERIC Educational Resources Information Center

    Administrative Office of the United States Courts, Washington, DC.

    This booklet discusses the workings of the federal courts and supports six law-related lesson plans. It is divided into the following sections: "The Constitution and the Federal Judiciary"; "The Federal Courts in American Government" ("The Federal Courts and Congress"; "The Federal Courts and the Executive Branch"; "The Federal Courts and the…

  13. Implications of deregulation in natural gas industry on utility risks and returns

    NASA Astrophysics Data System (ADS)

    Addepalli, Rajendra P.

    This thesis examines the changes in risk and required return on capital for local distribution utility companies in the increasingly competitive natural gas industry. The deregulation in the industry impacts the LDCs in several ways. First, with the introduction of competition consumers have been given choices among suppliers besides the traditional monopoly, the local utility, for purchasing their natural gas supply needs. Second, with the introduction of competition, some of the interstate pipelines were stuck with 'Take Or Pay' contracts and other costs that resulted in 'stranded costs', which have been passed on to customers of the pipeline including the LDCs. Third, the new obligation for the LDCs to purchase gas from the market, as opposed to buying it from pipelines and passing on the costs to its customers, brought opportunities and risks as well. Finally, with the introduction of competition, in some states LDCs have been allowed to enter into unregulated ventures to increase their profits. In the thesis we first develop a multifactor model (MFM) to explain historical common stock returns of individual utilities and of utility portfolios. We use 'rolling regression' analysis to analyze how different variables explain the variation in stock returns over time. Second, we conduct event studies to analyze the events in the deregulation process that had significant impacts on the LDC returns. Finally we assess the changes in risk and required return on capital for the LDCs over a 15 year time frame, covering the deregulation period. We employ four aspects in the examination of risk and return profile of the utilities: measuring (a) changes in required return on common equity and Weighted Average Cost of Capital, (b) changes in risk premium (WACC less an interest rate proxy), (c) changes in utility bond ratings, and (d) changes in dividend payments, new debt and equity issuances. We perform regression analysis to explain the changes in the required WACC using

  14. MicroRNA deregulation in cancer cells and the tumor microenvironment

    PubMed Central

    Rupaimoole, Rajesha; Calin, George A.; Lopez-Berestein, Gabriel; Sood, Anil K.

    2015-01-01

    MicroRNAs (miRNAs) are a key component of the noncoding RNA family. The underlying mechanisms involved in the interplay between the tumor microenvironment and cancer cells involve highly dynamic factors such as hypoxia and cell types such as cancer-associated fibroblasts and macrophages. Although miRNA levels are known to be altered in cancer cells, recent evidence suggests a critical role for the tumor microenvironment in regulating miRNA biogenesis, methylation, and transcriptional changes. Here, we discuss the complex pro-tumorigenic symbiotic role between tumor cells, the tumor microenvironment, and miRNA deregulation. PMID:26865249

  15. AGC System after Deregulation Considering TCPS in Series with the Tie-Line

    NASA Astrophysics Data System (ADS)

    Abraham, Rajesh Joseph; Das, D.; Patra, A.

    2015-06-01

    This paper presents the study of automatic generation control (AGC) of two area interconnected power system after deregulation, considering a thyristor controlled phase shifter (TCPS) in series with the tie-line. It is possible to minimize the system frequency and tie-power oscillations by controlling the phase angle of TCPS which is expected to provide a new ancillary service for the future power system. Effect of TCPS is examined for three different cases, i.e. (1) unilateral contract, (2) bilateral contract and (3) contract violation. Analysis reveals that a TCPS is quite capable of suppressing the frequency and tie-power oscillations effectively as compared to that obtained without TCPS.

  16. Genetics and metabolic deregulation following cancer initiation: A world to explore.

    PubMed

    Araldi, Rodrigo Pinheiro; Módolo, Diego Grando; de Sá Júnior, Paulo Luiz; Consonni, Sílvio Roberto; de Carvalho, Rodrigo Franco; Roperto, Franco Peppino; Beçak, Willy; de Cassia Stocco, Rita

    2016-08-01

    Cancer is a group of highly complex and heterogeneous diseases with several causes. According to the stochastic model, cancer initiates from mutation in somatic cells, leading to genomic instability and cell transformation. This canonical pathway of carcinogenesis is related to the discovery of important mechanisms that regulate cancer initiation. However, there are few studies describing genetic and metabolic alterations that deregulate transformed cells, resulting in epithelial-mesenchymal transition (EMT) and its most dramatic consequence, the metastasis. This review summarizes the main genetics and metabolic changes induced by reactive oxygen species (ROS) that lead to EMT. PMID:27470384

  17. And deregulation shall lead me to lie down in green pastures

    SciTech Connect

    Weidinger, G.

    1995-06-01

    This presentation briefly reviews the history of the IPP industry, the current state of competition, and potential opportunities for IPPs in a deregulated environment. Since the beginning of the PURPA created IPP industry, we have experienced many market phases. These began with {open_quotes}beat avoided cost,{close_quotes} followed by {open_quotes}find a need and fill it,{close_quotes} followed by {open_quotes}the bid fest,{close_quotes} to today`s {open_quotes}anything goes.{close_quotes} During this time, market clearing prices have declined from over 80/KwHr to 2-40/KwHr. Today`s partially deregulated electric market includes fierce competition and several new players in the game. Where surplus capacity exists, IPPs must compete with subsidized power. Long-term contracts are no longer widely available. Access to markets is constrained by less than open transmission. Even with these challenges, opportunities remain for the IPP supplier. Opportunities for advanced coal-fired power systems will be explored.

  18. BPA-Induced Deregulation Of Epigenetic Patterns: Effects On Female Zebrafish Reproduction.

    PubMed

    Santangeli, Stefania; Maradonna, Francesca; Gioacchini, Giorgia; Cobellis, Gilda; Piccinetti, Chiara Carla; Dalla Valle, Luisa; Carnevali, Oliana

    2016-01-01

    Bisphenol A (BPA) is one of the commonest Endocrine Disruptor Compounds worldwide. It interferes with vertebrate reproduction, possibly by inducing deregulation of epigenetic mechanisms. To determine its effects on female reproductive physiology and investigate whether changes in the expression levels of genes related to reproduction are caused by histone modifications, BPA concentrations consistent with environmental exposure were administered to zebrafish for three weeks. Effects on oocyte growth and maturation, autophagy and apoptosis processes, histone modifications, and DNA methylation were assessed by Real-Time PCR (qPCR), histology, and chromatin immunoprecipitation combined with qPCR analysis (ChIP-qPCR). The results showed that 5 μg/L BPA down-regulated oocyte maturation-promoting signals, likely through changes in the chromatin structure mediated by histone modifications, and promoted apoptosis in mature follicles. These data indicate that the negative effects of BPA on the female reproductive system may be due to its upstream ability to deregulate epigenetic mechanism.

  19. Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma.

    PubMed

    Snijders, Antoine M; Schmidt, Brian L; Fridlyand, Jane; Dekker, Nusi; Pinkel, Daniel; Jordan, Richard C K; Albertson, Donna G

    2005-06-16

    Genomes of solid tumors are characterized by gains and losses of regions, which may contribute to tumorigenesis by altering gene expression. Often the aberrations are extensive, encompassing whole chromosome arms, which makes identification of candidate genes in these regions difficult. Here, we focused on narrow regions of gene amplification to facilitate identification of genetic pathways important in oral squamous cell carcinoma (SCC) development. We used array comparative genomic hybridization (array CGH) to define minimum common amplified regions and then used expression analysis to identify candidate driver genes in amplicons that spanned <3 Mb. We found genes involved in integrin signaling (TLN1), survival (YAP1, BIRC2), and adhesion and migration (TLN1, LAMA3, MMP7), as well as members of the hedgehog (GLI2) and notch (JAG1, RBPSUH, FJX1) pathways to be amplified and overexpressed. Deregulation of these and other members of the hedgehog and notch pathways (HHIP, SMO, DLL1, NOTCH4) implicates deregulation of developmental and differentiation pathways, cell fate misspecification, in oral SCC development. PMID:15824737

  20. BPA-Induced Deregulation Of Epigenetic Patterns: Effects On Female Zebrafish Reproduction.

    PubMed

    Santangeli, Stefania; Maradonna, Francesca; Gioacchini, Giorgia; Cobellis, Gilda; Piccinetti, Chiara Carla; Dalla Valle, Luisa; Carnevali, Oliana

    2016-01-01

    Bisphenol A (BPA) is one of the commonest Endocrine Disruptor Compounds worldwide. It interferes with vertebrate reproduction, possibly by inducing deregulation of epigenetic mechanisms. To determine its effects on female reproductive physiology and investigate whether changes in the expression levels of genes related to reproduction are caused by histone modifications, BPA concentrations consistent with environmental exposure were administered to zebrafish for three weeks. Effects on oocyte growth and maturation, autophagy and apoptosis processes, histone modifications, and DNA methylation were assessed by Real-Time PCR (qPCR), histology, and chromatin immunoprecipitation combined with qPCR analysis (ChIP-qPCR). The results showed that 5 μg/L BPA down-regulated oocyte maturation-promoting signals, likely through changes in the chromatin structure mediated by histone modifications, and promoted apoptosis in mature follicles. These data indicate that the negative effects of BPA on the female reproductive system may be due to its upstream ability to deregulate epigenetic mechanism. PMID:26911650

  1. The proteomic signature of NPM/ALK reveals deregulation of multiple cellular pathways.

    PubMed

    Lim, Megan S; Carlson, Mary L; Crockett, David K; Fillmore, G Chris; Abbott, David R; Elenitoba-Johnson, Olaotan F; Tripp, Sheryl R; Rassidakis, George Z; Medeiros, L Jeffrey; Szankasi, Philippe; Elenitoba-Johnson, Kojo S J

    2009-08-20

    Constitutive expression of the chimeric NPM/ALK fusion protein encoded by the t(2;5)(p32;q35) is a key oncogenic event in the pathogenesis of most anaplastic large cell lymphomas (ALCLs). The proteomic network alterations produced by this aberration remain largely uncharacterized. Using a mass spectrometry (MS)-driven approach to identify changes in protein expression caused by the NPM/ALK fusion, we identified diverse NPM/ALK-induced changes affecting cell proliferation, ribosome synthesis, survival, apoptosis evasion, angiogenesis, and cytoarchitectural organization. MS-based findings were confirmed using Western blotting and/or immunostaining of NPM/ALK-transfected cells and ALK-deregulated lymphomas. A subset of the proteins distinguished NPM/ALK-positive ALCLs from NPM/ALK-negative ALCLs and Hodgkin lymphoma. The multiple NPM/ALK-deregulated pathways identified by MS analysis also predicted novel biologic effects of NPM/ALK expression. In this regard, we showed loss of cell adhesion as a consequence of NPM/ALK expression in a kinase-dependent manner, and sensitivity of NPM/ALK-positive ALCLs to inhibition of the RAS, p42/44ERK, and FRAP/mTOR signaling pathways. These findings reveal that the NPM/ALK alteration affects diverse cellular pathways, and provide novel insights into NPM/ALK-positive ALCL pathobiology. Our studies carry important implications for the use of MS-driven approaches for the elucidation of neoplastic pathobiology, the identification of novel diagnostic biomarkers, and pathogenetically relevant therapeutic targets.

  2. SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia

    PubMed Central

    Pearson, Helen B.; Perez-Mancera, Pedro A.; Dow, Lukas E.; Ryan, Andrew; Tennstedt, Pierre; Bogani, Debora; Elsum, Imogen; Greenfield, Andy; Tuveson, David A.; Simon, Ronald; Humbert, Patrick O.

    2011-01-01

    Loss of cellular polarity is a hallmark of epithelial cancers, raising the possibility that regulators of polarity have a role in suppressing tumorigenesis. The Scribble complex is one of at least three interacting protein complexes that have a critical role in establishing and maintaining epithelial polarity. In human colorectal, breast, and endometrial cancers, expression of the Scribble complex member SCRIB is often mislocalized and deregulated. Here, we report that Scrib is indispensable for prostate homeostasis in mice. Scrib heterozygosity initiated prostate hyperplasia, while targeted biallelic Scrib loss predisposed mice to prostate intraepithelial neoplasia. Mechanistically, Scrib was shown to negatively regulate the MAPK cascade to suppress tumorigenesis. Further analysis revealed that prostate-specific loss of Scrib in mice combined with expression of an oncogenic Kras mutation promoted the progression of prostate cancer that recapitulated the human disease. The clinical significance of the work in mice was highlighted by our observation that SCRIB deregulation strongly correlated with poor survival in human prostate cancer. These data suggest that the polarity network could provide a new avenue for therapeutic intervention. PMID:21965329

  3. Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing.

    PubMed

    Galanos, Panagiotis; Vougas, Konstantinos; Walter, David; Polyzos, Alexander; Maya-Mendoza, Apolinar; Haagensen, Emma J; Kokkalis, Antonis; Roumelioti, Fani-Marlen; Gagos, Sarantis; Tzetis, Maria; Canovas, Begoña; Igea, Ana; Ahuja, Akshay K; Zellweger, Ralph; Havaki, Sofia; Kanavakis, Emanuel; Kletsas, Dimitris; Roninson, Igor B; Garbis, Spiros D; Lopes, Massimo; Nebreda, Angel; Thanos, Dimitris; Blow, J Julian; Townsend, Paul; Sørensen, Claus Storgaard; Bartek, Jiri; Gorgoulis, Vassilis G

    2016-07-01

    The cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4-CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery-an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs. PMID:27323328

  4. Integrative Genome-Scale Analysis Identifies Epigenetic Mechanisms of Transcriptional Deregulation in Unfavorable Neuroblastomas.

    PubMed

    Henrich, Kai-Oliver; Bender, Sebastian; Saadati, Maral; Dreidax, Daniel; Gartlgruber, Moritz; Shao, Chunxuan; Herrmann, Carl; Wiesenfarth, Manuel; Parzonka, Martha; Wehrmann, Lea; Fischer, Matthias; Duffy, David J; Bell, Emma; Torkov, Alica; Schmezer, Peter; Plass, Christoph; Höfer, Thomas; Benner, Axel; Pfister, Stefan M; Westermann, Frank

    2016-09-15

    The broad clinical spectrum of neuroblastoma ranges from spontaneous regression to rapid progression despite intensive multimodal therapy. This diversity is not fully explained by known genetic aberrations, suggesting the possibility of epigenetic involvement in pathogenesis. In pursuit of this hypothesis, we took an integrative approach to analyze the methylomes, transcriptomes, and copy number variations in 105 cases of neuroblastoma, complemented by primary tumor- and cell line-derived global histone modification analyses and epigenetic drug treatment in vitro We found that DNA methylation patterns identify divergent patient subgroups with respect to survival and clinicobiologic variables, including amplified MYCN Transcriptome integration and histone modification-based definition of enhancer elements revealed intragenic enhancer methylation as a mechanism for high-risk-associated transcriptional deregulation. Furthermore, in high-risk neuroblastomas, we obtained evidence for cooperation between PRC2 activity and DNA methylation in blocking tumor-suppressive differentiation programs. Notably, these programs could be re-activated by combination treatments, which targeted both PRC2 and DNA methylation. Overall, our results illuminate how epigenetic deregulation contributes to neuroblastoma pathogenesis, with novel implications for its diagnosis and therapy. Cancer Res; 76(18); 5523-37. ©2016 AACR. PMID:27635046

  5. The impact of deregulation on the board structure of electric utilities

    NASA Astrophysics Data System (ADS)

    Wollan, Patricia L.

    This study analyzes the impact of deregulation on board structure by comparing the boards of electric utilities before and after the passage of the Energy Policy Act (EPACT). In addition, the study assesses whether board structure has an impact on firm performance during the period of transition. I find that electric utilities do change their board structure in response to their new operating environment. Boards are smaller and more independent in the later period. Also, even though the number of outside directors stays the same, there are notable changes in the character of these directors. The number of executives from large firms and the number of directors with political backgrounds are both significantly greater after the passage of EPACT. These results are consistent with Williamson's hypothesis that firms will change the composition and character of their board in response to a change in the firm's operating environment. Further investigation reveals that even though utilities' boards change following deregulation, the pace of change is slow, and during the four-year period immediately following the passage of EPACT firm performance is related to board character. These results suggest that while firms reconfigure their boards in response to a change in their operating environment, there may be impediments that prevent them from adjusting their boards too quickly.

  6. Transcriptome and small RNA deep sequencing reveals deregulation of miRNA biogenesis in human glioma.

    PubMed

    Moore, Lynette M; Kivinen, Virpi; Liu, Yuexin; Annala, Matti; Cogdell, David; Liu, Xiuping; Liu, Chang-Gong; Sawaya, Raymond; Yli-Harja, Olli; Shmulevich, Ilya; Fuller, Gregory N; Zhang, Wei; Nykter, Matti

    2013-02-01

    Altered expression of oncogenic and tumour-suppressing microRNAs (miRNAs) is widely associated with tumourigenesis. However, the regulatory mechanisms underlying these alterations are poorly understood. We sought to shed light on the deregulation of miRNA biogenesis promoting the aberrant miRNA expression profiles identified in these tumours. Using sequencing technology to perform both whole-transcriptome and small RNA sequencing of glioma patient samples, we examined precursor and mature miRNAs to directly evaluate the miRNA maturation process, and examined expression profiles for genes involved in the major steps of miRNA biogenesis. We found that ratios of mature to precursor forms of a large number of miRNAs increased with the progression from normal brain to low-grade and then to high-grade gliomas. The expression levels of genes involved in each of the three major steps of miRNA biogenesis (nuclear processing, nucleo-cytoplasmic transport, and cytoplasmic processing) were systematically altered in glioma tissues. Survival analysis of an independent data set demonstrated that the alteration of genes involved in miRNA maturation correlates with survival in glioma patients. Direct quantification of miRNA maturation with deep sequencing demonstrated that deregulation of the miRNA biogenesis pathway is a hallmark for glioma genesis and progression.

  7. Transcriptome and Small RNA Deep Sequencing Reveals Deregulation of miRNA Biogenesis in Human Glioma

    PubMed Central

    Moore, Lynette M.; Kivinen, Virpi; Liu, Yuexin; Annala, Matti; Cogdell, David; Liu, Xiuping; Liu, Chang-Gong; Sawaya, Raymond; Yli-Harja, Olli; Shmulevich, Ilya; Fuller, Gregory N.; Zhang, Wei; Nykter, Matti

    2013-01-01

    Altered expression of oncogenic and tumor-suppressing microRNAs (miRNAs) is widely associated with tumorigenesis. However, the regulatory mechanisms underlying these alterations are poorly understood. We sought to shed light on the deregulation of miRNA biogenesis promoting the aberrant miRNA expression profiles identified in these tumors. Using sequencing technology to perform both whole-transcriptome and small RNA sequencing of glioma patient samples, we examined precursor and mature miRNAs to directly evaluate the miRNA maturation process, and interrogated expression profiles for genes involved in the major steps of miRNA biogenesis. We found that ratios of mature to precursor forms of a large number of miRNAs increased with the progression from normal brain to low-grade and then to high-grade gliomas. The expression levels of genes involved in each of the three major steps of miRNA biogenesis (nuclear processing, nucleo-cytoplasmic transport, and cytoplasmic processing) were systematically altered in glioma tissues. Survival analysis of an independent data set demonstrated that the alteration of genes involved in miRNA maturation correlates with survival in glioma patients. Direct quantification of miRNA maturation with deep sequencing demonstrated that deregulation of the miRNA biogenesis pathway is a hallmark for glioma genesis and progression. PMID:23007860

  8. Deregulation of the miRNAs Expression in Cervical Cancer: Human Papillomavirus Implications

    PubMed Central

    Gómez-Gómez, Yazmín; Organista-Nava, Jorge; Gariglio, Patricio

    2013-01-01

    MicroRNAs (miRNAs) are a class of small non coding RNAs of 18–25 nucleotides in length. The temporal or short-lived expression of the miRNAs modulates gene expression post transcriptionally. Studies have revealed that miRNAs deregulation correlates and is involved with the initiation and progression of human tumors. Cervical cancer (CC) displays notably increased or decreased expression of a large number of cellular oncogenic or tumor suppressive miRNAs, respectively. However, understanding the potential role of miRNAs in CC is still limited. In CC, the high-risk human papillomaviruses (HR-HPVs) infection can affect the miRNAs expression through oncoprotein E6 and E7 that contribute to viral pathogenesis, although other viral proteins might also be involved. This deregulation in the miRNAs expression has an important role in the hallmarks of CC. Interestingly, the miRNA expression profile in CC can discriminate between normal and tumor tissue and the extraordinary stability of miRNAs makes it suitable to serve as diagnostic and prognostic biomarkers of cancer. In this review, we will summarize the role of the HR-HPVs in miRNA expression, the role of miRNAs in the hallmarks of CC, and the use of miRNAs as potential prognostic biomarkers in CC. PMID:24490161

  9. BPA-Induced Deregulation Of Epigenetic Patterns: Effects On Female Zebrafish Reproduction

    PubMed Central

    Santangeli, Stefania; Maradonna, Francesca; Gioacchini, Giorgia; Cobellis, Gilda; Piccinetti, Chiara Carla; Dalla Valle, Luisa; Carnevali, Oliana

    2016-01-01

    Bisphenol A (BPA) is one of the commonest Endocrine Disruptor Compounds worldwide. It interferes with vertebrate reproduction, possibly by inducing deregulation of epigenetic mechanisms. To determine its effects on female reproductive physiology and investigate whether changes in the expression levels of genes related to reproduction are caused by histone modifications, BPA concentrations consistent with environmental exposure were administered to zebrafish for three weeks. Effects on oocyte growth and maturation, autophagy and apoptosis processes, histone modifications, and DNA methylation were assessed by Real-Time PCR (qPCR), histology, and chromatin immunoprecipitation combined with qPCR analysis (ChIP-qPCR). The results showed that 5 μg/L BPA down-regulated oocyte maturation-promoting signals, likely through changes in the chromatin structure mediated by histone modifications, and promoted apoptosis in mature follicles. These data indicate that the negative effects of BPA on the female reproductive system may be due to its upstream ability to deregulate epigenetic mechanism. PMID:26911650

  10. HTLV-1 Tax deregulates autophagy by recruiting autophagic molecules into lipid raft microdomains.

    PubMed

    Ren, T; Takahashi, Y; Liu, X; Loughran, T P; Sun, S-C; Wang, H-G; Cheng, H

    2015-01-15

    The retroviral oncoprotein Tax from human T-cell leukemia virus type 1 (HTLV-1), an etiological factor that causes adult T-cell leukemia and lymphoma, has a crucial role in initiating T-lymphocyte transformation by inducing oncogenic signaling activation. We here report that Tax is a determining factor for dysregulation of autophagy in HTLV-1-transformed T cells and Tax-immortalized CD4 memory T cells. Tax facilitated autophagic process by activating inhibitor of κB (IκB) kinase (IKK) complex, which subsequently recruited an autophagy molecular complex containing Beclin1 and Bif-1 to the lipid raft microdomains. Tax engaged a crosstalk between IKK complex and autophagic molecule complex by directly interacting with both complexes, promoting assembly of LC3+ autophagosomes. Moreover, expression of lipid raft-targeted Bif-1 or Beclin1 was sufficient to induce formation of LC3+ autophagosomes, suggesting that Tax recruitment of autophagic molecules to lipid rafts is a dominant strategy to deregulate autophagy in the context of HTLV-1 transformation of T cells. Furthermore, depletion of autophagy molecules such as Beclin1 and PI3 kinase class III resulted in impaired growth of HTLV-1-transformed T cells, indicating a critical role of Tax-deregulated autophagy in promoting survival and transformation of virally infected T cells.

  11. Deregulation of the miRNAs expression in cervical cancer: human papillomavirus implications.

    PubMed

    Gómez-Gómez, Yazmín; Organista-Nava, Jorge; Gariglio, Patricio

    2013-01-01

    MicroRNAs (miRNAs) are a class of small non coding RNAs of 18-25 nucleotides in length. The temporal or short-lived expression of the miRNAs modulates gene expression post transcriptionally. Studies have revealed that miRNAs deregulation correlates and is involved with the initiation and progression of human tumors. Cervical cancer (CC) displays notably increased or decreased expression of a large number of cellular oncogenic or tumor suppressive miRNAs, respectively. However, understanding the potential role of miRNAs in CC is still limited. In CC, the high-risk human papillomaviruses (HR-HPVs) infection can affect the miRNAs expression through oncoprotein E6 and E7 that contribute to viral pathogenesis, although other viral proteins might also be involved. This deregulation in the miRNAs expression has an important role in the hallmarks of CC. Interestingly, the miRNA expression profile in CC can discriminate between normal and tumor tissue and the extraordinary stability of miRNAs makes it suitable to serve as diagnostic and prognostic biomarkers of cancer. In this review, we will summarize the role of the HR-HPVs in miRNA expression, the role of miRNAs in the hallmarks of CC, and the use of miRNAs as potential prognostic biomarkers in CC.

  12. Copper-induced deregulation of microRNA expression in the zebrafish olfactory system

    PubMed Central

    Wang, Lu; Bammler, Theo K.; Beyer, Richard P.; Gallagher, Evan P.

    2016-01-01

    Although environmental trace metals, such as copper (Cu), can disrupt normal olfactory function in fish, the underlying molecular mechanisms of metal-induced olfactory injury have not been elucidated. Current research has suggested the involvement of epigenetic modifications. To address this hypothesis, we analyzed microRNA (miRNA) profiles in the olfactory system of Cu-exposed zebrafish. Our data revealed 2, 10, and 28 differentially expressed miRNAs in a dose-response manner corresponding to three increasing Cu concentrations. Numerous deregulated miRNAs were involved in neurogenesis (e.g. let-7, miR-7a, miR-128 and miR-138), indicating a role for Cu-mediated toxicity via interference with neurogenesis processes. Putative gene targets of deregulated miRNAs were identified when interrogating our previously published microarray database, including those involved in cell growth and proliferation, cell death, and cell morphology. Moreover, several miRNAs (e.g. miR-203a, miR-199*, miR-16a, miR-16c, and miR-25) may contribute to decreased mRNA levels of their host genes involved in olfactory signal transduction pathways and other critical neurological processes via a post-transcriptional mechanism. Our findings provide novel insight into the epigenetic regulatory mechanisms of metal-induced neurotoxicity of the fish olfactory system, and identify novel miRNA biomarkers of metal exposures. PMID:23745839

  13. Deregulated c-myc expression overrides IFN gamma-induced macrophage growth arrest.

    PubMed

    Vairo, G; Vadiveloo, P K; Royston, A K; Rockman, S P; Rock, C O; Jackowski, S; Hamilton, J A

    1995-05-18

    Induction of c-myc gene expression is an essential response to growth promoting agents, including colony-stimulating factor 1 (CSF-1). Down regulation of c-myc expression occurs in response to a variety of negative growth regulators in many cell types. However, for many of these systems the causal link between c-myc down regulation and growth arrest remains to be established. Here we show for CSF-1-dependent BAC1.2F5 mouse macrophages that interferon-gamma (IFN gamma) results in a midlate G1 phase decrease of CSF-1-dependent c-myc mRNA and subsequent cell cycle arrest. Introduction of a deregulated c-myc gene into these cells, which prevents the IFN gamma-mediated decrease in c-myc expression, overrides the cell cycle arrest and restores CSF-1-dependent growth in the presence of the cytokine. This result contrasts with the macrophage growth arrest induced by cAMP elevation, which also suppresses c-myc expression, but is not overcome by a deregulated c-myc gene. These results show that inhibition of c-myc expression is an essential component in IFN gamma-mediated cell cycle arrest and demonstrates that distinct mechanisms contribute to IFN gamma- and cAMP-mediated growth arrest in macrophages.

  14. The impact of deregulation and restructuring: An empirical case study of the electric utility industry from 1998 through 2007

    NASA Astrophysics Data System (ADS)

    Robinson, Deborah E.

    This qualitative study analyzed the residential electricity prices in the competitive U.S. electric market from 1998 to 2007. This analysis revealed that electricity restructuring has not yet resulted in lower prices for the majority of residential consumers in areas open to competition. This study reviewed actual experiences of eight states in the deregulated and restructured electricity markets: Illinois, Maine, Massachusetts, New Hampshire, Nevada, Pennsylvania, Rhode Island, and Virginia. The study began with a historical look at the deregulated and restructured electricity market from 1990 to 2007. The electricity market was deregulated to include retail competition and price caps. The results indicated that both had an effect on residential prices. This study used data from the Energy Information Administration and the 8 public utility commissions. Contrary to common expectations, residential electricity costs for consumers have increased rather than decreased.

  15. Ronald Reagan's "New Federalism."

    ERIC Educational Resources Information Center

    Parker, Joseph B.

    1982-01-01

    Describes how changes in federal fiscal policies affect the federal government's relationship to state and local government. Franklin D. Roosevelt's and Ronald Reagan's formulas for "New Federalism" are compared. (AM)

  16. Hearing on the Impact of Deregulation on the American Workers. Hearing before the Committee on Education and Labor. House of Representatives, One Hundredth Congress, First Session (Miami, Florida).

    ERIC Educational Resources Information Center

    Congress of the U.S., Washington, DC. House Committee on Education and Labor.

    This congressional report includes testimony pertaining to the impact of the Reagan administration's policy of increased deregulation on American workers. Particular emphasis is placed on the impact that deregulation has had on specific occupations, industries (including plant closings), wage structures, and organized labor. The following…

  17. Deregulation of intestinal anti-microbial defense by the dietary additive, maltodextrin

    PubMed Central

    Nickerson, Kourtney P; Chanin, Rachael; McDonald, Christine

    2015-01-01

    Inflammatory bowel disease (IBD) is a complex, multi-factorial disease thought to arise from an inappropriate immune response to commensal bacteria in a genetically susceptible person that results in chronic, cyclical, intestinal inflammation. Dietary and environmental factors are implicated in the initiation and perpetuation of IBD; however, a singular causative agent has not been identified. As of now, the role of environmental priming or triggers in IBD onset and pathogenesis are not well understood, but these factors appear to synergize with other disease susceptibility factors. In previous work, we determined that the polysaccharide dietary additive, maltodextrin (MDX), impairs cellular anti-bacterial responses and suppresses intestinal anti-microbial defense mechanisms. In this addendum, we review potential mechanisms for dietary deregulation of intestinal homeostasis, postulate how dietary and genetic risk factors may combine to result in disease pathogenesis, and discuss these ideas in the context of recent findings related to dietary interventions for IBD. PMID:25738413

  18. CCT`s in a deregulated environment: A producer`s perspective

    SciTech Connect

    Edmonds, R.F. Jr.; Fayssoux, J.O.

    1997-12-31

    The US electric industry will be deregulated (or substantially re-regulated) within 5 years. Several states, including California, Rhode Island, and New Hampshire, already have passed legislation to introduce competition into the electric markets before the year 2000. As this trend sweeps across the country, the resulting competitive market for generation will reward the lowest cost producers and force high cost producers out of the market. As a result, at least in the short run, it may be very difficult for new power plants employing Clean Coal Technologies (CCTs) to compete. This paper discusses a producer`s perspective of the new competitive market, and suggests several short and long term strategies and niches for CCTs.

  19. The role of clean coal technologies in a deregulated rural utility market

    SciTech Connect

    Neal, J.W.

    1997-12-31

    The nation`s rural electric cooperatives own a high proportion of coal-fired generation, in excess of 80 percent of their generating capacity. As the electric utility industry moves toward a competitive electricity market, the generation mix for electric cooperatives is expected to change. Distributed generation will likely serve more customer loads than is now the case, and that will lead to an increase in gas-fired generation capacity. But, clean low-cost central station coal-fired capacity is expected to continue to be the primary source of power for growing rural electric cooperatives. Gasification combined cycle could be the lowest cost coal based generation option in this new competitive market if both capital cost and electricity production costs can be further reduced. This paper presents anticipated utility business scenarios for the deregulated future and identifies combined cycle power plant configurations that might prove most competitive.

  20. DEK Expression is controlled by E2F and deregulated in diverse tumor types.

    PubMed

    Carro, Maria Stella; Spiga, Fabio Mario; Quarto, Micaela; Di Ninni, Valentina; Volorio, Sara; Alcalay, Myriam; Müller, Heiko

    2006-06-01

    Deregulation of the retinoblastoma (pRB) tumor suppressor pathway associated with aberrant activity of E2F transcription factors is frequently observed in human cancer. Microarray based analyses have revealed a large number of potential downstream mediators of the tumor suppressing activity of pRB, including DEK, a fusion partner of CAN found in a subset of acute myeloid leukaemia (AML) patients carrying a (6; 9) translocation. Here we report that the expression of DEK is under direct control of E2F transcription factors. Chromatin immunoprecipitation assays show that the DEK promoter is bound by endogenous E2F in vivo. The DEK promoter is transactivated by E2F and mutation of E2F binding sites eliminates this effect. Expression levels of DEK in human tumors have been investigated by tissue micro array analysis. We find that DEK is overexpressed in many solid tumors such as colon cancer, larynx cancer, bladder cancer, and melanoma.

  1. MYCN deregulation as a potential target for novel therapies in rhabdomyosarcoma.

    PubMed

    Morgenstern, Daniel A; Anderson, John

    2006-02-01

    Rhabdomyosarcoma is the most common soft-tissue sarcoma of childhood. Treatment requires a multimodality approach combining chemotherapy with surgery and radiotherapy. Although overall outcomes have improved considerably, the outlook for patients with high-risk disease, particularly the alveolar subtype, remains bleak and there is a clear need for new chemotherapeutic strategies. This review focuses on the possibilities for interventions targeting myc myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN). The importance of aberrant expression of this oncogene is well established in neuroblastoma and recent data indicate that MYCN deregulation also occurs in up to a quarter of alveolar subtype cases. A range of possible approaches to target MYCN is discussed, including nucleic acid-based and immunotherapy strategies.

  2. Deregulated repression of c-Jun provides a potential link to its role in tumorigenesis.

    PubMed

    Weiss, Carsten; Bohmann, Dirk

    2004-02-01

    The transcription factor c-Jun cooperates with oncogenic alleles of ras in malignant transformation. Constitutively active Ras causes, via activation of mitogen activated protein kinases, phosphorylation of c-Jun which is essential for subsequent target gene activation and tumorigenesis. Studying the mechanisms controlling c-Jun activity we found that its transcription activation function is actively repressed by a presumably multimeric repressor complex that includes histone deacetylase 3 as a critical subunit. Suppression of c-Jun is relieved by MAP kinase-mediated phosphorylation and/or titration of inhibitor components. The viral tumorigenic counterpart of c-Jun, v-Jun, escapes this inhibition, suggesting deregulated transcriptional activity of c-Jun as a relevant cause for carcinogenesis.

  3. Amplification of Distant Estrogen Response Elements Deregulates Target Genes Associated with Tamoxifen Resistance in Breast Cancer

    PubMed Central

    Hsu, Pei-Yin; Hsu, Hang-Kai; Lan, Xun; Juan, Liran; Yan, Pearlly S.; Labanowska, Jadwiga; Heerema, Nyla; Hsiao, Tzu-Hung; Chiu, Yu-Chiao; Chen, Yidong; Liu, Yunlong; Li, Lang; Li, Rong; Thompson, Ian M.; Nephew, Kenneth P.; Sharp, Zelton D.; Kirma, Nameer B.; Jin, Victor X.; Huang, Tim H.-M.

    2013-01-01

    SUMMARY A causal role of gene amplification in tumorigenesis is well-known, while amplification of DNA regulatory elements as an oncogenic driver remains unclear. In this study, we integrated next-generation sequencing approaches to map distant estrogen response elements (DEREs) that remotely control transcription of target genes through chromatin proximity. Two densely mapped DERE regions located on chromosomes 17q23 and 20q13 were frequently amplified in ERα-positive luminal breast cancer. These aberrantly amplified DEREs deregulated target gene expression potentially linked to cancer development and tamoxifen resistance. Progressive accumulation of DERE copies was observed in normal breast progenitor cells chronically exposed to estrogenic chemicals. These findings may extend to other DNA regulatory elements, the amplification of which can profoundly alter target transcriptome during tumorigenesis. PMID:23948299

  4. A Novel Approach of Battery Energy Storage for Improving Value of Wind Power in Deregulated Markets

    NASA Astrophysics Data System (ADS)

    Nguyen, Y. Minh; Yoon, Yong Tae

    2013-06-01

    Wind power producers face many regulation costs in deregulated environment, which remarkably lowers the value of wind power in comparison with the conventional sources. One of these costs is associated with the real-time variation of power output and being paid in frequency control market according to the variation band. In this regard, this paper presents a new approach to the scheduling and operation of battery energy storage installed in wind generation system. This approach depends on the statistic data of wind generation and the prediction of frequency control market prices to determine the optimal charging and discharging of batteries in real-time, which ultimately gives the minimum cost of frequency regulation for wind power producers. The optimization problem is formulated as the trade-off between the decrease in regulation payment and the increase in the cost of using battery energy storage. The approach is illustrated in the case study and the results of simulation show its effectiveness.

  5. Control requirements for cogen and microgen plants in a deregulated electricity industry

    SciTech Connect

    Shavit, G.

    2000-07-01

    The deregulation of the electricity production and distribution industry provides opportunities and concerns to the end-users as well as to the electricity producing companies. The end-user objective is to get a reliable source of electrical energy at the lowest rate possible. On the other hand, the primary objective of the three providing companies--generation, transmission, and local distribution--is to profit while satisfying their customers' needs. These three companies may compete for the same customer, and new competitors may enter the arena. The existing technology of the cogeneration plant and the emergence of the microgenerating plant will be used by all the providers and by the end-users to achieve their objectives. The purpose of this paper is to introduce the concept of operation of the microgenerating plant, to identify the requirements of each interested player, and to introduce control strategies.

  6. Allocation of Transaction Cost to Market Participants Using an Analytical Method in Deregulated Market

    NASA Astrophysics Data System (ADS)

    Jeyasankari, S.; Jeslin Drusila Nesamalar, J.; Charles Raja, S.; Venkatesh, P.

    2014-04-01

    Transmission cost allocation is one of the major challenges in transmission open access faced by the electric power sector. The purpose of this work is to provide an analytical method for allocating transmission transaction cost in deregulated market. This research work provides a usage based transaction cost allocation method based on line-flow impact factor (LIF) which relates the power flow in each line with respect to transacted power for the given transaction. This method provides the impact of line flows without running iterative power flow solution and is well suited for real time applications. The proposed method is compared with the Newton-Raphson (NR) method of cost allocation on sample six bus and practical Indian utility 69 bus systems by considering multilateral transaction.

  7. Deregulation of intestinal anti-microbial defense by the dietary additive, maltodextrin.

    PubMed

    Nickerson, Kourtney P; Chanin, Rachael; McDonald, Christine

    2015-01-01

    Inflammatory bowel disease (IBD) is a complex, multi-factorial disease thought to arise from an inappropriate immune response to commensal bacteria in a genetically susceptible person that results in chronic, cyclical, intestinal inflammation. Dietary and environmental factors are implicated in the initiation and perpetuation of IBD; however, a singular causative agent has not been identified. As of now, the role of environmental priming or triggers in IBD onset and pathogenesis are not well understood, but these factors appear to synergize with other disease susceptibility factors. In previous work, we determined that the polysaccharide dietary additive, maltodextrin (MDX), impairs cellular anti-bacterial responses and suppresses intestinal anti-microbial defense mechanisms. In this addendum, we review potential mechanisms for dietary deregulation of intestinal homeostasis, postulate how dietary and genetic risk factors may combine to result in disease pathogenesis, and discuss these ideas in the context of recent findings related to dietary interventions for IBD.

  8. Autophagy: a druggable process that is deregulated in aging and human disease

    PubMed Central

    Kroemer, Guido

    2015-01-01

    Autophagy (“self-eating”) constitutes one of the most spectacular yet subtly regulated phenomena in cell biology. Similarly to cell division, differentiation, and death, autophagy is perturbed in multiple diseases, in that excessive or deficient autophagy may contribute to pathogenesis. Numerous attempts have been launched to identify specific inducers or inhibitors of autophagy and to use them for the therapeutic correction of its deregulation. At present, several major disease categories (including but not limited to age-related, cardiovascular, infectious, neoplastic, neurodegenerative, and metabolic pathologies) are being investigated for pathogenic aberrations in autophagy and their pharmacologic rectification. Driven by promising preclinical results, several clinical trials are exploring autophagy as a therapeutic target. PMID:25654544

  9. Neoplastic transformation of mouse mammary epithelial cells by deregulated myc expression.

    PubMed Central

    Telang, N T; Osborne, M P; Sweterlitsch, L A; Narayanan, R

    1990-01-01

    A spontaneously immortalized, nontumorigenic mouse mammary epithelial cell line (MMEC) was transfected with an activated myc construct by electroporation. Constitutive expression of myc in MMEC resulted in anchorage independence in soft agar and tumorigenicity in nude mice. The myc-expressing MMEC showed higher saturation density, faster growth rate, and partial abrogation of serum-derived growth factor(s) requirement compared with parent MMEC. Epidermal growth factor or transforming growth factor alpha stimulated the anchorage-independent growth, but not the anchorage-dependent growth, of MMEC-myc cells. Type 1 transforming growth factor beta, on the other hand, inhibited both the anchorage-independent and anchorage-dependent growth of MMEC-myc cells. These results demonstrate that deregulated expression of myc results in neoplastic transformation iin mammary epithelial cells. Accompanying the transformation is altered sensitivity to polypeptide growth factors. Images PMID:2088530

  10. Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

    PubMed Central

    Eisinger-Mathason, T. S. Karin; Mucaj, Vera; Biju, Kevin M.; Nakazawa, Michael S.; Gohil, Mercy; Cash, Timothy P.; Yoon, Sam S.; Skuli, Nicolas; Park, Kyung Min; Gerecht, Sharon; Simon, M. Celeste

    2015-01-01

    Genetic aberrations responsible for soft-tissue sarcoma formation in adults are largely unknown, with targeted therapies sorely needed for this complex and heterogeneous family of diseases. Here we report that that the Hippo pathway is deregulated in many soft-tissue sarcomas, resulting in elevated expression of the effector molecule Yes-Associated Protein (YAP). Based on data gathered from human sarcoma patients, a novel autochthonous mouse model, and mechanistic analyses, we determined that YAP-dependent expression of the transcription factor forkhead box M1 (FOXM1) is necessary for cell proliferation/tumorigenesis in a subset of soft-tissue sarcomas. Notably, FOXM1 directly interacts with the YAP transcriptional complex via TEAD1, resulting in coregulation of numerous critical pro-proliferation targets that enhance sarcoma progression. Finally, pharmacologic inhibition of FOXM1 decreases tumor size in vivo, making FOXM1 an attractive therapeutic target for the treatment of some sarcoma subtypes. PMID:26080399

  11. MMPs/TIMPs and inflammatory signalling de-regulation in human incisional hernia tissues

    PubMed Central

    Guillen-Marti, Jordi; Diaz, Ramon; Quiles, Maria T; Lopez-Cano, Manuel; Vilallonga, Ramon; Huguet, Pere; Ramon-y-Cajal, Santiago; Sanchez-Niubo, Albert; Reventós, Jaume; Armengol, Manel; Arbos, Maria A

    2009-01-01

    Background: Incisional hernia is a common and important complication of laparotomies. Epidemiological studies allude to an underlying biological cause, at least in a subset of population. Interest has mainly focused on abnormal collagen metabolism. However, the role played by other determinants of extracellular matrix (ECM) composition is unknown. To date, there are few laboratory studies investigating the importance of biological factors contributing to incisional hernia development. We performed a descriptive tissue-based analysis to elucidate the possible relevance of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in association with local cytokine induction in human incisional hernia tissues. The expression profiles of MMPs, TIMPs and pro-inflammatory cytokine signalling were investigated in aponeurosis and skeletal muscle specimens taken intraoperatively from incisional hernia (n= 10) and control (n= 10) patients. Semiquantitative RT-PCR, zymography and immunoblotting analyses were done. Incisional hernia samples displayed alterations in the microstructure and loss of ECM, as assessed by histological analyses. Moreover, incisional hernia tissues showed increased MMP/TIMP ratios and de-regulated inflammatory signalling (tumor necrosis factor [TNFA] and interleukin [IL]-6 tended to increase, whereas aponeurosis TNFA receptors decreased). The changes were tissue-specific and were detectable at the mRNA and/or protein level. Statistical analyses showed several associations between individual MMPs, TIMPs, interstitial collagens and inflammatory markers. The increment of MMPs in the absence of a counterbalance by TIMPs, together with an ongoing de-regulated inflammatory signalling, may contribute in inducing a functional defect of the ECM network by post-translational mechanisms, which may trigger abdominal wall tissue loss and eventual rupture. The notable TIMP3 protein down-regulation in incisional hernia fascia may be of pathophysiological

  12. Patterns of Deregulation of Insulin Growth Factor Signaling Pathway in Pediatric and Adult Gastrointestinal Stromal Tumors

    PubMed Central

    Italiano, Antoine; Chen, Junwei; Zhang, Lei; Hajdu, Mihai; Singer, Samuel; DeMatteo, Ronald P; Antonescu, Cristina R.

    2013-01-01

    Background Data regarding the patterns and the mechanisms of deregulation of the insulin growth factor (IGF) pathway in adult and pediatric gastrointestinal stromal tumors (GISTs) are limited. Methods We investigated the expression profiling of the genes encoding the main components of the IGF signaling pathway in 131 GISTs (106 adult, 21 pediatric and 4 young adult) and 25 other soft-tissue sarcomas (STS) using an Affymetrix U133A platform. IGF2 was investigated for loss of imprinting (LOI) whereas IGF1R was analyzed for copy number aberration and mutation. Results IGF2 was the most highly overexpressed gene of the IGF pathway in GIST. IGF2 expression was also significantly higher than in other STS. IGF2 expression was correlated to the age onset and mutational status of GIST. Indeed, IGF2 expression was significantly higher in the “adult” group than in the “pediatric” and “young adult” groups. Among adult GIST, IGF2 expression was higher in tumors lacking KIT or PDGFRA mutations in comparison with mutated cases. A trend for a higher expression of IGF2 in resistant GIST in comparison to responsive GIST was also found. Overexpression of IGF2 was not related to LOI. Conversely, the expression of the IGF1R gene was significantly higher in the pediatric group than in the adult group. No copy number gains or mutations of IGF1R were observed. Conclusion The IGF pathway is deregulated in GIST with distinct patterns according to age onset and mutational status. The IGF pathway may represent a therapeutic target in patients with primary or secondary resistance to imatinib. PMID:22770876

  13. Integrated Computing, Communication, and Distributed Control of Deregulated Electric Power Systems

    SciTech Connect

    Bajura, Richard; Feliachi, Ali

    2008-09-24

    Restructuring of the electricity market has affected all aspects of the power industry from generation to transmission, distribution, and consumption. Transmission circuits, in particular, are stressed often exceeding their stability limits because of the difficulty in building new transmission lines due to environmental concerns and financial risk. Deregulation has resulted in the need for tighter control strategies to maintain reliability even in the event of considerable structural changes, such as loss of a large generating unit or a transmission line, and changes in loading conditions due to the continuously varying power consumption. Our research efforts under the DOE EPSCoR Grant focused on Integrated Computing, Communication and Distributed Control of Deregulated Electric Power Systems. This research is applicable to operating and controlling modern electric energy systems. The controls developed by APERC provide for a more efficient, economical, reliable, and secure operation of these systems. Under this program, we developed distributed control algorithms suitable for large-scale geographically dispersed power systems and also economic tools to evaluate their effectiveness and impact on power markets. Progress was made in the development of distributed intelligent control agents for reliable and automated operation of integrated electric power systems. The methodologies employed combine information technology, control and communication, agent technology, and power systems engineering in the development of intelligent control agents for reliable and automated operation of integrated electric power systems. In the event of scheduled load changes or unforeseen disturbances, the power system is expected to minimize the effects and costs of disturbances and to maintain critical infrastructure operational.

  14. Glutamate-induced deregulation of calcium homeostasis and mitochondrial dysfunction in mammalian central neurones.

    PubMed

    Khodorov, Boris

    2004-10-01

    Delayed neuronal death following prolonged (10-15 min) stimulation of Glu receptors is known to depend on sustained elevation of cytosolic Ca(2+) concentration ([Ca(2+)](i)) which may persist far beyond the termination of Glu exposure. Mitochondrial depolarization (MD) plays a central role in this Ca(2+) deregulation: it inhibits the uniporter-mediated Ca(2+) uptake and reverses ATP synthetase which enhances greatly ATP consumption during Glu exposure. MD-induced inhibition of Ca(2+) uptake in the face of continued Ca(2+) influx through Glu-activated channels leads to a secondary increase of [Ca(2+)](i) which, in its turn, enhances MD and thus [Ca(2+)](i). Antioxidants fail to suppress this pathological regenerative process which indicates that reactive oxygen species are not involved in its development. In mature nerve cells (>11 DIV), the post-glutamate [Ca(2+)](i) plateau associated with profound MD usually appears after 10-15 min Glu (100 microM) exposure. In contrast, in young cells (<9 DIV) delayed Ca(2+) deregulation (DCD) occurs only after 30-60 min Glu exposure. This difference is apparently determined by a dramatic increase in the susceptibility of mitochondia to Ca(2+) overload during nerve cells maturation. The exact mechanisms of Glu-induced profound MD and its coupling with the impairment of Ca(2+) extrusion following toxic Glu challenge is not clarified yet. Their elucidation demands a study of dynamic changes in local concentrations of ATP, Ca(2+), H(+), Na(+) and protein kinase C using novel methodological approaches. PMID:15288761

  15. The implications of deregulation for biomass and renewable energy in California

    SciTech Connect

    Morris, G

    1998-07-01

    California has been leading the nation down the path of electric utility deregulation, beginning with the April 1994, California Public Utilities Commission`s (CPUC) Blue Book restructuring proposal. The road for renewable energy producers has been particularly rocky, leaving the future of renewable energy production very much in doubt. The original CPUC proposal provided for competition among generating sources on the basis of price alone, without regard for environmental considerations. The California legislature took up electric utility deregulation legislation during 1996, culminating in AB 1890, California`s landmark restructuring legislation, which was passed unanimously by the Senate and Assembly, and signed into law by the governor on September 28, 1996. AB 1890 assigned to the California Energy Commission (CEC) the task of determining how to allocate the renewables transition funds between existing and new renewable generating sources, and among the various renewable energy technologies that are available for deployment in California. The California Environmental Protection Agency (Cal/EPA) was assigned the task of reporting to the legislature about the specific benefits provided by biomass energy production in California, and about policies that could shift some of the cost of biomass energy production away from the electric ratepayer, on to beneficiaries of the environmental benefits of biomass energy production. This study describes the development of the CEC and Cal/EPA reports to the California legislature, and provides an analysis of the major issues that were encountered during the course of their development. The study concludes with a consideration of the future prospects for biomass and renewable energy production in the state.

  16. Deregulated Expression of Aurora Kinases Is Not a Prognostic Biomarker in Papillary Thyroid Cancer Patients

    PubMed Central

    Prinzi, Natalie; Sorrenti, Salvatore; Falvo, Laura; De Vito, Corrado; Catania, Antonio; Tartaglia, Francesco; Mocini, Renzo; Coccaro, Carmela; Alessandrini, Stefania; Barollo, Susi; Mian, Caterina; Antonelli, Alessandro; De Antoni, Enrico; D’Armiento, Massimino; Ulisse, Salvatore

    2015-01-01

    A number of reports indicated that Aurora-A or Aurora-B overexpression represented a negative prognostic factor in several human malignancies. In thyroid cancer tissues a deregulated expression of Aurora kinases has been also demonstrated, butno information regarding its possible prognostic role in differentiated thyroid cancer is available. Here, weevaluated Aurora-A and Aurora-B mRNA expression and its prognostic relevance in a series of 87 papillary thyroid cancers (PTC), with a median follow-up of 63 months. The analysis of Aurora-A and Aurora-B mRNA levels in PTC tissues, compared to normal matched tissues, revealed that their expression was either up- or down-regulatedin the majority of cancer tissues. In particular, Aurora-A and Aurora-B mRNA levels were altered, respectively, in 55 (63.2%) and 79 (90.8%) out of the 87 PTC analyzed.A significant positive correlation between Aurora-A and Aurora-B mRNAswas observed (p=0.001). The expression of both Aurora genes was not affected by the BRAFV600E mutation. Univariate, multivariate and Kaplan-Mayer analyses documented the lack of association between Aurora-A or Aurora-B expression and clinicopathological parameterssuch as gender, age, tumor size, histology, TNM stage, lymph node metastasis and BRAF status as well asdisease recurrences or disease-free interval. Only Aurora-B mRNA was significantly higher in T(3-4) tissues, with respect to T(1-2) PTC tissues. The data reported here demonstrate that the expression of Aurora kinases is deregulated in the majority of PTC tissues, likely contributing to PTC progression. However, differently from other human solid cancers, detection of Aurora-A or Aurora-B mRNAs is not a prognostic biomarker inPTC patients. PMID:25807528

  17. Pleiotropic effects of methionine adenosyltransferases deregulation as determinants of liver cancer progression and prognosis.

    PubMed

    Frau, Maddalena; Feo, Francesco; Pascale, Rosa M

    2013-10-01

    Downregulation of liver-specific MAT1A gene, encoding S-adenosylmethionine (SAM) synthesizing isozymes MATI/III, and upregulation of widely expressed MAT2A, encoding MATII isozyme, known as MAT1A:MAT2A switch, occurs in hepatocellular carcinoma (HCC). Being inhibited by its reaction product, MATII isoform upregulation cannot compensate for MATI/III decrease. Therefore, MAT1A:MAT2A switch contributes to decrease in SAM level in rodent and human hepatocarcinogenesis. SAM administration to carcinogen-treated rats prevents hepatocarcinogenesis, whereas MAT1A-KO mice, characterized by chronic SAM deficiency, exhibit macrovesicular steatosis, mononuclear cell infiltration in periportal areas, and HCC development. This review focuses upon the pleiotropic changes, induced by MAT1A/MAT2A switch, associated with HCC development. Epigenetic control of MATs expression occurs at transcriptional and post-transcriptional levels. In HCC cells, MAT1A/MAT2A switch is associated with global DNA hypomethylation, decrease in DNA repair, genomic instability, and signaling deregulation including c-MYC overexpression, rise in polyamine synthesis, upregulation of RAS/ERK, IKK/NF-kB, PI3K/AKT, and LKB1/AMPK axis. Furthermore, decrease in MAT1A expression and SAM levels results in increased HCC cell proliferation, cell survival, and microvascularization. All of these changes are reversed by SAM treatment in vivo or forced MAT1A overexpression or MAT2A inhibition in cultured HCC cells. In human HCC, MAT1A:MAT2A and MATI/III:MATII ratios correlate negatively with cell proliferation and genomic instability, and positively with apoptosis and global DNA methylation. This suggests that SAM decrease and MATs deregulation represent potential therapeutic targets for HCC. Finally, MATI/III:MATII ratio strongly predicts patients' survival length suggesting that MAT1A:MAT2A expression ratio is a putative prognostic marker for human HCC.

  18. Federal Student Loan Programs

    ERIC Educational Resources Information Center

    Federal Student Aid, US Department of Education, 2014

    2014-01-01

    For those needing a loan to attend college, think federal aid first. Federal student loans usually offer borrowers lower interest rates and have more flexible repayment terms and options than private student loans. This brief report answers the following questions about federal aid: (1) What is a federal student loan?; (2) What is a private…

  19. Deregulation of microRNAs by HIV-1 Vpr Protein Leads to the Development of Neurocognitive Disorders*

    PubMed Central

    Mukerjee, Ruma; Chang, J. Robert; Del Valle, Luis; Bagashev, Asen; Gayed, Monika M.; Lyde, Randolph B.; Hawkins, Brian J.; Brailoiu, Eugen; Cohen, Eric; Power, Chris; Azizi, S. Ausim; Gelman, Benjamin B.; Sawaya, Bassel E.

    2011-01-01

    Studies have shown that HIV-infected patients develop neurocognitive disorders characterized by neuronal dysfunction. The lack of productive infection of neurons by HIV suggests that viral and cellular proteins, with neurotoxic activities, released from HIV-1-infected target cells can cause this neuronal deregulation. The viral protein R (Vpr), a protein encoded by HIV-1, has been shown to alter the expression of various important cytokines and inflammatory proteins in infected and uninfected cells; however the mechanisms involved remain unclear. Using a human neuronal cell line, we found that Vpr can be taken up by neurons causing: (i) deregulation of calcium homeostasis, (ii) endoplasmic reticulum-calcium release, (iii) activation of the oxidative stress pathway, (iv) mitochondrial dysfunction and v- synaptic retraction. In search for the cellular factors involved, we performed microRNAs and gene array assays using human neurons (primary cultures or cell line, SH-SY5Y) that we treated with recombinant Vpr proteins. Interestingly, Vpr deregulates the levels of several microRNAs (e.g. miR-34a) and their target genes (e.g. CREB), which could lead to neuronal dysfunctions. Therefore, we conclude that Vpr plays a major role in neuronal dysfunction through deregulating microRNAs and their target genes, a phenomenon that could lead to the development of neurocognitive disorders. PMID:21816823

  20. Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma

    PubMed Central

    Mathas, Stephan; Kreher, Stephan; Meaburn, Karen J.; Jöhrens, Korinna; Lamprecht, Björn; Assaf, Chalid; Sterry, Wolfram; Kadin, Marshall E.; Daibata, Masanori; Joos, Stefan; Hummel, Michael; Stein, Harald; Janz, Martin; Anagnostopoulos, Ioannis; Schrock, Evelin; Misteli, Tom; Dörken, Bernd

    2009-01-01

    Although the identification and characterization of translocations have rapidly increased, little is known about the mechanisms of how translocations occur in vivo. We used anaplastic large cell lymphoma (ALCL) with and without the characteristic t(2;5)(p23;q35) translocation to study the mechanisms of formation of translocations and of ALCL transformation. We report deregulation of several genes located near the ALCL translocation breakpoint, regardless of whether the tumor contains the t(2;5). The affected genes include the oncogenic transcription factor Fra2 (located on 2p23), the HLH protein Id2 (2p25), and the oncogenic tyrosine kinase CSF1-receptor (5q33.1). Their up-regulation promotes cell survival and repression of T cell-specific gene expression programs that are characteristic for ALCL. The deregulated genes are in spatial proximity within the nuclear space of t(2;5)-negative ALCL cells, facilitating their translocation on induction of double-strand breaks. These data suggest that deregulation of breakpoint-proximal genes occurs before the formation of translocations, and that aberrant transcriptional activity of genomic regions is linked to their propensity to undergo chromosomal translocations. Also, our data demonstrate that deregulation of breakpoint-proximal genes has a key role in ALCL. PMID:19321746

  1. Deregulation of microRNAs by HIV-1 Vpr protein leads to the development of neurocognitive disorders.

    PubMed

    Mukerjee, Ruma; Chang, J Robert; Del Valle, Luis; Bagashev, Asen; Gayed, Monika M; Lyde, Randolph B; Hawkins, Brian J; Brailoiu, Eugen; Cohen, Eric; Power, Chris; Azizi, S Ausim; Gelman, Benjamin B; Sawaya, Bassel E

    2011-10-01

    Studies have shown that HIV-infected patients develop neurocognitive disorders characterized by neuronal dysfunction. The lack of productive infection of neurons by HIV suggests that viral and cellular proteins, with neurotoxic activities, released from HIV-1-infected target cells can cause this neuronal deregulation. The viral protein R (Vpr), a protein encoded by HIV-1, has been shown to alter the expression of various important cytokines and inflammatory proteins in infected and uninfected cells; however the mechanisms involved remain unclear. Using a human neuronal cell line, we found that Vpr can be taken up by neurons causing: (i) deregulation of calcium homeostasis, (ii) endoplasmic reticulum-calcium release, (iii) activation of the oxidative stress pathway, (iv) mitochondrial dysfunction and v- synaptic retraction. In search for the cellular factors involved, we performed microRNAs and gene array assays using human neurons (primary cultures or cell line, SH-SY5Y) that we treated with recombinant Vpr proteins. Interestingly, Vpr deregulates the levels of several microRNAs (e.g. miR-34a) and their target genes (e.g. CREB), which could lead to neuronal dysfunctions. Therefore, we conclude that Vpr plays a major role in neuronal dysfunction through deregulating microRNAs and their target genes, a phenomenon that could lead to the development of neurocognitive disorders.

  2. 26 CFR 1.168(i)-3 - Treatment of excess deferred income tax reserve upon disposition of deregulated public utility...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 2 2014-04-01 2014-04-01 false Treatment of excess deferred income tax reserve... INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES... income tax reserve upon disposition of deregulated public utility property. (a) Scope—(1) In...

  3. Deregulating School Aid in California: How 10 Districts Responded to Fiscal Flexibility, 2009-2010. Research Report Number 2

    ERIC Educational Resources Information Center

    Fuller, Bruce; Marsh, Julie A.; Stecher, Brian M.; Timar, Tom

    2011-01-01

    In 2009, California state legislators freed local educators from the specific guidelines that previously regulated spending on 40 categorical-aid programs known as Tier 3 programs. This Tier 3 flexibility reform, which deregulates $4.5 billion in education funding, was enacted at the same time the legislature made cuts in education spending in…

  4. Neural network based load and price forecasting and confidence interval estimation in deregulated power markets

    NASA Astrophysics Data System (ADS)

    Zhang, Li

    With the deregulation of the electric power market in New England, an independent system operator (ISO) has been separated from the New England Power Pool (NEPOOL). The ISO provides a regional spot market, with bids on various electricity-related products and services submitted by utilities and independent power producers. A utility can bid on the spot market and buy or sell electricity via bilateral transactions. Good estimation of market clearing prices (MCP) will help utilities and independent power producers determine bidding and transaction strategies with low risks, and this is crucial for utilities to compete in the deregulated environment. MCP prediction, however, is difficult since bidding strategies used by participants are complicated and MCP is a non-stationary process. The main objective of this research is to provide efficient short-term load and MCP forecasting and corresponding confidence interval estimation methodologies. In this research, the complexity of load and MCP with other factors is investigated, and neural networks are used to model the complex relationship between input and output. With improved learning algorithm and on-line update features for load forecasting, a neural network based load forecaster was developed, and has been in daily industry use since summer 1998 with good performance. MCP is volatile because of the complexity of market behaviors. In practice, neural network based MCP predictors usually have a cascaded structure, as several key input factors need to be estimated first. In this research, the uncertainties involved in a cascaded neural network structure for MCP prediction are analyzed, and prediction distribution under the Bayesian framework is developed. A fast algorithm to evaluate the confidence intervals by using the memoryless Quasi-Newton method is also developed. The traditional back-propagation algorithm for neural network learning needs to be improved since MCP is a non-stationary process. The extended Kalman

  5. The MAPK1/3 pathway is essential for the deregulation of autophagy observed in G2019S LRRK2 mutant fibroblasts

    PubMed Central

    Bravo-San Pedro, José M.; Gómez-Sánchez, Rubén; Niso-Santano, Mireia; Pizarro-Estrella, Elisa; Aiastui-Pujana, Ana; Gorostidi, Ana; Climent, Vicente; López de Maturana, Rakel; Sanchez-Pernaute, Rosario; López de Munain, Adolfo; Fuentes, José M.; González-Polo, Rosa A.

    2012-01-01

    The link between the deregulation of autophagy and cell death processes can be essential in the development of several neurodegenerative diseases, such as Parkinson disease (PD). However, the molecular mechanism of deregulation of this degradative process in PD patients is unknown. The leucine-rich repeat kinase 2 (LRRK2) gene is related to PD and its implication in autophagy regulation has been described. Our recent work shows that the presence of the G2019S LRRK2 mutation, one of the most prevalent in LRRK2, is accompanied by a deregulation of autophagy basal levels dependent on the MAPK1/3 (ERK2/1) pathway. PMID:22914360

  6. The Federal Role

    ERIC Educational Resources Information Center

    Davidson, Robert H.; Stark, Joan S.

    1976-01-01

    Traces emerging federal policy that constitutes a multidimensional attack on abuses of the educational consumer (involving Congress, the Office of Education, the Federal Trade Commission, Veterans Administration, Postal Service, and Bureau of Indian Affairs) aimed primarily at protecting federal investments. (Editor/JT)

  7. 75 FR 68321 - Forage Genetics International; Supplemental Request for Partial Deregulation of Roundup Ready...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-05

    ... FR 68300-68301, Docket No. 04-085-1) announcing receipt of a petition from the Monsanto Company... completion of the EA, we published another notice in the Federal Register on June 27, 2005 (70 FR 36917-36919... intent to prepare an EIS in the Federal Register on January 7, 2008 (73 FR 1198-1200, Docket No....

  8. Wrecked regulation of intrinsically disordered proteins in diseases: pathogenicity of deregulated regulators

    PubMed Central

    Uversky, Vladimir N.

    2014-01-01

    Biologically active proteins without stable tertiary structure are common in all known proteomes. Functions of these intrinsically disordered proteins (IDPs) are typically related to regulation, signaling, and control. Cellular levels of these important regulators are tightly regulated by a variety mechanisms ranging from firmly controlled expression to precisely targeted degradation. Functions of IDPs are controlled by binding to specific partners, alternative splicing, and posttranslational modifications among other means. In the norm, right amounts of precisely activated IDPs have to be present in right time at right places. Wrecked regulation brings havoc to the ordered world of disordered proteins, leading to protein misfolding, misidentification, and missignaling that give rise to numerous human diseases, such as cancer, cardiovascular disease, neurodegenerative diseases, and diabetes. Among factors inducing pathogenic transformations of IDPs are various cellular mechanisms, such as chromosomal translocations, damaged splicing, altered expression, frustrated posttranslational modifications, aberrant proteolytic degradation, and defective trafficking. This review presents some of the aspects of deregulated regulation of IDPs leading to human diseases. PMID:25988147

  9. Beyond the histone tale: HP1α deregulation in breast cancer epigenetics.

    PubMed

    Vad-Nielsen, Johan; Nielsen, Anders Lade

    2015-01-01

    Heterochromatin protein 1α (HP1α) encoded from the CBX5-gene is an evolutionary conserved protein that binds histone H3 di- or tri-methylated at position lysine 9 (H3K9me2/3), a hallmark for heterochromatin, and has an essential role in forming higher order chromatin structures. HP1α has diverse functions in heterochromatin formation, gene regulation, and mitotic progression, and forms complex networks of gene, RNA, and protein interactions. Emerging evidence has shown that HP1α serves a unique biological role in breast cancer related processes and in particular for epigenetic control mechanisms involved in aberrant cell proliferation and metastasis. However, how HP1α deregulation plays dual mechanistic functions for cancer cell proliferation and metastasis suppression and the underlying cellular mechanisms are not yet comprehensively described. In this paper we provide an overview of the role of HP1α as a new sight of epigenetics in proliferation and metastasis of human breast cancer. This highlights the importance of addressing HP1α in breast cancer diagnostics and therapeutics. PMID:25588111

  10. Beyond the histone tale: HP1α deregulation in breast cancer epigenetics

    PubMed Central

    Vad-Nielsen, Johan; Nielsen, Anders Lade

    2015-01-01

    Heterochromatin protein 1α (HP1α) encoded from the CBX5-gene is an evolutionary conserved protein that binds histone H3 di- or tri-methylated at position lysine 9 (H3K9me2/3), a hallmark for heterochromatin, and has an essential role in forming higher order chromatin structures. HP1α has diverse functions in heterochromatin formation, gene regulation, and mitotic progression, and forms complex networks of gene, RNA, and protein interactions. Emerging evidence has shown that HP1α serves a unique biological role in breast cancer related processes and in particular for epigenetic control mechanisms involved in aberrant cell proliferation and metastasis. However, how HP1α deregulation plays dual mechanistic functions for cancer cell proliferation and metastasis suppression and the underlying cellular mechanisms are not yet comprehensively described. In this paper we provide an overview of the role of HP1α as a new sight of epigenetics in proliferation and metastasis of human breast cancer. This highlights the importance of addressing HP1α in breast cancer diagnostics and therapeutics. PMID:25588111

  11. Human Papillomavirus Deregulates the Response of a Cellular Network Comprising of Chemotactic and Proinflammatory Genes

    PubMed Central

    Karim, Rezaul; Meyers, Craig; Backendorf, Claude; Ludigs, Kristina; Offringa, Rienk; van Ommen, Gert-Jan B.; Melief, Cornelis J. M.; van der Burg, Sjoerd H.; Boer, Judith M.

    2011-01-01

    Despite the presence of intracellular pathogen recognition receptors that allow infected cells to attract the immune system, undifferentiated keratinocytes (KCs) are the main targets for latent infection with high-risk human papilloma viruses (hrHPVs). HPV infections are transient but on average last for more than one year suggesting that HPV has developed means to evade host immunity. To understand how HPV persists, we studied the innate immune response of undifferentiated human KCs harboring episomal copies of HPV16 and 18 by genome-wide expression profiling. Our data showed that the expression of the different virus-sensing receptors was not affected by the presence of HPV. Poly(I:C) stimulation of the viral RNA receptors TLR3, PKR, MDA5 and RIG-I, the latter of which indirectly senses viral DNA through non-self RNA polymerase III transcripts, showed dampening in downstream signalling of these receptors by HPVs. Many of the genes downregulated in HPV-positive KCs involved components of the antigen presenting pathway, the inflammasome, the production of antivirals, pro-inflammatory and chemotactic cytokines, and components downstream of activated pathogen receptors. Notably, gene and/or protein interaction analysis revealed the downregulation of a network of genes that was strongly interconnected by IL-1β, a crucial cytokine to activate adaptive immunity. In summary, our comprehensive expression profiling approach revealed that HPV16 and 18 coordinate a broad deregulation of the keratinocyte's inflammatory response, and contributes to the understanding of virus persistence. PMID:21423754

  12. Apolipoprotein E gene polymorphism influences aggressive behavior in prostate cancer cells by deregulating cholesterol homeostasis

    PubMed Central

    IFERE, GODWIN O.; DESMOND, RENEE; DEMARK-WAHNEFRIED, WENDY; NAGY, TIM R.

    High circulating cholesterol and its deregulated homeostasis may facilitate prostate cancer progression. Genetic polymorphism in Apolipoprotein (Apo) E, a key cholesterol regulatory protein may effect changes in systemic cholesterol levels. In this investigation, we determined whether variants of the Apo E gene can trigger defective intracellular cholesterol efflux, which could promote aggressive prostate cancer. ApoE genotypes of weakly (non-aggressive), moderate and highly tumorigenic (aggressive) prostate cancer cell lines were characterized, and we explored whether the ApoE variants were associated with tumor aggressiveness generated by intra cellular cholesterol imbalance, using the expression of caveolin-1 (cav-1), a pro-malignancy surrogate of cholesterol overload. Restriction isotyping of ApoE isoforms revealed that the non-aggressive cell lines carried ApoE ε3/ε3 or ε3/ε4 alleles, while the aggressive cell lines carried the Apoε2/ε4 alleles. Our data suggest a contrast between the non-aggressive and the aggressive prostate cancer cell lines in the pattern of cholesterol efflux and cav-1 expression. Our exploratory results suggest a relationship between prostate aggressiveness, ApoE isoforms and cholesterol imbalance. Further investigation of this relationship may elucidate the molecular basis for considering cholesterol as a risk factor of aggressive prostate tumors, and underscore the potential of the dysfunctional ApoE2/E4 isoform as a biomarker of aggressive disease. PMID:23934233

  13. Image is all: Deregulation, restructuring and reputation in the natural gas industry

    SciTech Connect

    1997-09-01

    Does image affect how one views his local utility company--or energy supplier? Does one value his utility companies more if one sees a lot of image advertising and public relations stories about community involvement, environmental action and charitable work? Or does one view utilities as faceless and anonymous entities that provide necessary services one thinks little about until there`s a problem? And, more important, what is the role of utility image in an era of deregulation, as companies begin a new scramble for customers? To find an answer to these questions, American Gas and Christopher Bonner Consultants conducted a survey of A.G.A. member companies to learn what, if anything, utility companies are doing in the areas of image assessment and change. The survey was sent to more than 200 A.G.A. member companies; written responses were received from 35. In addition, 13 follow-up telephone interviews were conducted, including four with companies that had not responded in writing. The picture that emerges if of an industry that is starting to pay greater and greater attention to image. And, as utilities reorganize and redefine themselves, they are also reexamining the ways they communicate with key audiences, including employees, customers, legislators, the financial community and the news media.

  14. Deregulation of miR-183 and KIAA0101 in Aggressive and Malignant Pituitary Tumors

    PubMed Central

    Roche, Magali; Wierinckx, Anne; Croze, Séverine; Rey, Catherine; Legras-Lachuer, Catherine; Morel, Anne-Pierre; Fusco, Alfredo; Raverot, Gérald; Trouillas, Jacqueline; Lachuer, Joel

    2015-01-01

    Changes in microRNAs (miRNAs) expression in many types of cancer suggest that they may be involved in crucial steps during tumor progression. Indeed, miRNAs deregulation has been described in pituitary tumorigenesis, but few studies have described their role in pituitary tumor progression toward aggressiveness and malignancy. To assess the role of miRNAs within the hierarchical cascade of events in prolactin (PRL) tumors during progression, we used an integrative genomic approach to associate clinical–pathological features, global miRNA expression, and transcriptomic profiles of the same human tumors. We describe the specific down-regulation of one principal miRNA, miR-183, in the 8 aggressive (A, grade 2b) compared to the 18 non-aggressive (NA, grades 1a, 2a) PRL tumors. We demonstrate that it acts as an anti-proliferative gene by directly targeting KIAA0101, which is involved in cell cycle activation and inhibition of p53–p21-mediated cell cycle arrest. Moreover, we show that miR-183 and KIAA0101 expression significantly correlate with the main markers of pituitary tumors aggressiveness, Ki-67 and p53. These results confirm the activation of proliferation in aggressive and malignant PRL tumors compared to non-aggressive ones. Importantly, these data also demonstrate the ability of such an integrative genomic strategy, applied in the same human tumors, to identify the molecular mechanisms responsible for tumoral progression even from a small cohort of patients. PMID:26322309

  15. Direct targeting of Arabidopsis cysteine synthase complexes with synthetic polypeptides to selectively deregulate cysteine synthesis.

    PubMed

    Wawrzyńska, Anna; Kurzyk, Agata; Mierzwińska, Monika; Płochocka, Danuta; Wieczorek, Grzegorz; Sirko, Agnieszka

    2013-06-01

    Biosynthesis of cysteine is one of the fundamental processes in plants providing the reduced sulfur for cell metabolism. It is accomplished by the sequential action of two enzymes, serine acetyltransferase (SAT) and O-acetylserine (thiol) lyase (OAS-TL). Together they constitute the hetero-oligomeric cysteine synthase (CS) complex through specific protein-protein interactions influencing the rate of cysteine production. The aim of our studies was to deregulate the CS complex formation in order to investigate its function in the control of sulfur homeostasis and optimize cysteine synthesis. Computational modeling was used to build a model of the Arabidopsis thaliana mitochondrial CS complex. Several polypeptides based on OAS-TL C amino-acid sequence found at SAT-OASTL interaction sites were designed as probable competitors for SAT3 binding. After verification of the binding in a yeast two-hybrid assay, the most strongly interacting polypeptide was introduced to different cellular compartments of Arabidopsis cell via genetic transformation. Moderate increase in total SAT and OAS-TL activities, but not thiols content, was observed dependent on the transgenic line and sulfur availability in the hydroponic medium. Though our studies demonstrate the proof of principle, they also suggest more complex interaction of both enzymes underlying the mechanism of their reciprocal regulation. PMID:23602110

  16. CDX2-driven leukemogenesis involves KLF4 repression and deregulated PPARγ signaling

    PubMed Central

    Faber, Katrin; Bullinger, Lars; Ragu, Christine; Garding, Angela; Mertens, Daniel; Miller, Christina; Martin, Daniela; Walcher, Daniel; Döhner, Konstanze; Döhner, Hartmut; Claus, Rainer; Plass, Christoph; Sykes, Stephen M.; Lane, Steven W.; Scholl, Claudia; Fröhling, Stefan

    2012-01-01

    Aberrant expression of the homeodomain transcription factor CDX2 occurs in most cases of acute myeloid leukemia (AML) and promotes leukemogenesis, making CDX2, in principle, an attractive therapeutic target. Conversely, CDX2 acts as a tumor suppressor in colonic epithelium. The effectors mediating the leukemogenic activity of CDX2 and the mechanism underlying its context-dependent properties are poorly characterized, and strategies for interfering with CDX2 function in AML remain elusive. We report data implicating repression of the transcription factor KLF4 as important for the oncogenic activity of CDX2, and demonstrate that CDX2 differentially regulates KLF4 in AML versus colon cancer cells through a mechanism that involves tissue-specific patterns of promoter binding and epigenetic modifications. Furthermore, we identified deregulation of the PPARγ signaling pathway as a feature of CDX2-associated AML and observed that PPARγ agonists derepressed KLF4 and were preferentially toxic to CDX2+ leukemic cells. These data delineate transcriptional programs associated with CDX2 expression in hematopoietic cells, provide insight into the antagonistic duality of CDX2 function in AML versus colon cancer, and suggest reactivation of KLF4 expression, through modulation of PPARγ signaling, as a therapeutic modality in a large proportion of AML patients. PMID:23202735

  17. Head lice surveillance on a deregulated OTC-sales market: a study using web query data.

    PubMed

    Lindh, Johan; Magnusson, Måns; Grünewald, Maria; Hulth, Anette

    2012-01-01

    The head louse, Pediculus humanus capitis, is an obligate ectoparasite that causes infestations of humans. Studies have demonstrated a correlation between sales figures for over-the-counter (OTC) treatment products and the number of humans with head lice. The deregulation of the Swedish pharmacy market on July 1, 2009, decreased the possibility to obtain complete sale figures and thereby the possibility to obtain yearly trends of head lice infestations. In the presented study we wanted to investigate whether web queries on head lice can be used as substitute for OTC sales figures. Via Google Insights for Search and Vårdguiden medical web site, the number of queries on "huvudlöss" (head lice) and "hårlöss" (lice in hair) were obtained. The analysis showed that both the Vårdguiden series and the Google series were statistically significant (p<0.001) when added separately, but if the Google series were already included in the model, the Vårdguiden series were not statistically significant (p = 0.5689). In conclusion, web queries can detect if there is an increase or decrease of head lice infested humans in Sweden over a period of years, and be as reliable a proxy as the OTC-sales figures. PMID:23144923

  18. The implications of deregulation for biomass and renewable energy in California. Revision

    SciTech Connect

    Morris, G.

    1998-08-01

    The California legislature took up electric utility deregulation legislation during 1996, culminating in AB 1890, California`s landmark restructuring legislation. The legislation created a transition funding program for renewables. No permanent program for the support of renewable energy production extending beyond the end of the transition period (2002) is included in AB 1890. AB 1890 assigned to the California Energy Commission (CEC) the task of determining how to allocate the renewables transition funds between existing and new renewable generating sources, and among the various renewable energy technologies that are available for deployment in California. The California Environmental Protection Agency (Cal/EPA) was assigned the task of reporting to the legislature about the specific benefits provided by biomass energy production in California, and about policies that could shift some of the cost of biomass energy production away from the electric ratepayer, on to beneficiaries of the environmental benefits of biomass energy production. This study describes the development of the CEC and Cal/EPA reports to the California legislature, and provides an analysis of the major issues that were encountered during the course of their development. The study concludes with a consideration of the future prospects for biomass and renewable energy production in the state.

  19. Recessive genetic deregulation abrogates c-myc suppression by interferon and is implicated in oncogenesis

    SciTech Connect

    Kimchi, A.; Resnitzky, D.; Ber, R.; Gat, G.

    1988-07-01

    Previously the authors demonstrated that many hematopoietic tumor cells are resistant to the inhibitory effects that interferon exerts on c-myc mRNA expression without losing other receptor-mediated intracellular responses. They report here that this partial resistance was overridden in two independent stable somatic cell hybrids prepared by fusion between sensitive and resistant cells. The c-myc mRNA transcribed from the active allele of the resistant parent cell was reduced by interferon within the context of the cell hybrid. It was therefore concluded that changes in the cis-acting sequences of c-myc were not involved in this type of relaxed regulation and that resistance resulted rather from inactivation or loss of postreceptor elements which operate in trans. The growth-stimulating effect that this genetic deregulation might have on cells was tested in experimental systems of cell differentiation in which an autocrine interferon is produced. For that purpose the authors isolated variant clones of M1 myeloid cells which were partially resistant to alpha and beta interferons and tested their growth behaviour during in vitro-induced differentiation. The resistant clones displayed higher proliferative activity on days 2 and 3 of differentiation than did the sensitive clones, which stopped proliferating. The loss of c-myc responses to the self-produced interferon disrupted the normal cessation of growth during differentiation and therefore might lead cells along the pathway of neoplasia.

  20. hTERT, MYC and TP53 deregulation in gastric preneoplastic lesions

    PubMed Central

    2012-01-01

    Background Gastric cancer is a serious public health problem in Northern Brazil and in the world due to its high incidence and mortality. Despite the severity of the disease, more research is needed to better understand the molecular events involved in this intestinal-type gastric carcinogenesis process. Since precancerous lesions precede intestinal-type gastric cancer, here, we evaluated the hTERT, MYC, and TP53 mRNA and protein expression, as well as TP33 copy number, in gastric preneoplastic lesions. Methods We evaluated 19 superficial gastritis, 18 atrophic gastritis, and 18 intestinal metaplasia from cancer-free individuals of Northern Brazil. Quantitative reverse transcription PCR was used to analyze the mRNA expression and immunohistochemical methods were used to assess protein immunoreactivity in tissue samples. The number of TP53 gene copies was investigated in gastric diseases by quantitative PCR. Results We observed hTERT, MYC, and p53 immunoreactivity only in intestinal metaplasia samples. The immunoreactivity of these proteins was strongly associated with each other. A significantly higher MYC mRNA expression was observed in intestinal metaplasia compared to gastritis samples. Loss of TP53 was also only detected in intestinal metaplasia specimens. Conclusions We demonstrated that hTERT, MYC, and TP53 are deregulated in intestinal metaplasia of individuals from Northern Brazil and these alterations may facilitate tumor initiation. PMID:22768805

  1. Frequent occurrence of CCND1 deregulation in patients with early stages of plasma cell dyscrasia.

    PubMed

    Miura, Kazuhisa; Iida, Shinsuke; Hanamura, Ichiro; Kato, Miyuki; Banno, Shogo; Ishida, Takashi; Kusumoto, Shigeru; Takeuchi, Genji; Miwa, Hiroshi; Nitta, Masakazu; Inagaki, Hiroshi; Eimoto, Tadaaki; Nomura, Kenichi; Taniwaki, Masafumi; Ueda, Ryuzo

    2003-04-01

    Chromosomal translocations involving the immunoglobulin heavy chain gene (IgH) and nonrandom protooncogene loci are the hallmark of genetic alterations found not only in multiple myeloma (MM), but also in premalignant stages of MM, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). We studied the frequency of IgH (14q32) rearrangements and their partner chromosomes in 16 Japanese patients with MGUS (13 cases), and SMM (3 cases) by means of interphase double-color fluorescence in situ hybridization (DCFISH) applied to purified plasma cells and using CD138-bead selection. IgH rearrangement was recognized in nine of the patients (56.3%). Protooncogene loci juxtaposed to IgH were identified in seven cases including CCND1 (11q13) in six cases and FGFR3 (4p16) in one. Four out of the six t(11;14)-positive cases showed nuclear staining of the cyclin D1 protein, whereas none of the seven t(11;14)-negative cases did. Moreover, neither MUM1(6p25)-IgH nor MAFB(20q11)-IgH fusion signals were observed. This suggests to us that cyclin D1 deregulation due to the presence of t(11;14) is involved in the early development of plasma cell neoplasms, and that this event alone is not enough for the development of symptomatic myeloma. PMID:12824903

  2. Deregulation of mTOR signaling is involved in thymic lymphoma development in Atm-/- mice

    SciTech Connect

    Kuang, Xianghong; Shen, Jianjun; Wong, Paul K.Y.; Yan, Mingshan

    2009-06-05

    Abnormal thymocyte development with thymic lymphomagenesis inevitably occurs in Atm-/- mice, indicating that ATM plays a pivotal role in regulating postnatal thymocyte development and preventing thymic lymphomagenesis. The mechanism for ATM controls these processes is unclear. We have shown previously that c-Myc, an oncoprotein regulated by the mammalian target of rapamycin (mTOR), is overexpressed in Atm-/- thymocytes. Here, we show that inhibition of mTOR signaling with its specific inhibitor, rapamycin, suppresses normal thymocyte DNA synthesis by downregulating 4EBP1, but not S6K, and that 4EBP1 phosphorylation and cyclin D1 expression are coordinately increased in Atm-/- thymocytes. Administration of rapamycin to Atm-/- mice attenuates elevated phospho-4EBP1, c-Myc and cyclin D1 in their thymocytes, and delays thymic lymphoma development. These results indicate that mTOR downstream effector 4EBP1 is essential for normal thymocyte proliferation, but deregulation of 4EBP1 in Atm deficiency is a major factor driving thymic lymphomagenesis in the animals.

  3. Deregulation of Feedback Inhibition of Phosphoenolpyruvate Carboxylase for Improved Lysine Production in Corynebacterium glutamicum

    PubMed Central

    Chen, Zhen; Bommareddy, Rajesh Reddy; Frank, Doinita; Rappert, Sugima

    2014-01-01

    Allosteric regulation of phosphoenolpyruvate carboxylase (PEPC) controls the metabolic flux distribution of anaplerotic pathways. In this study, the feedback inhibition of Corynebacterium glutamicum PEPC was rationally deregulated, and its effect on metabolic flux redistribution was evaluated. Based on rational protein design, six PEPC mutants were designed, and all of them showed significantly reduced sensitivity toward aspartate and malate inhibition. Introducing one of the point mutations (N917G) into the ppc gene, encoding PEPC of the lysine-producing strain C. glutamicum LC298, resulted in ∼37% improved lysine production. In vitro enzyme assays and 13C-based metabolic flux analysis showed ca. 20 and 30% increases in the PEPC activity and corresponding flux, respectively, in the mutant strain. Higher demand for NADPH in the mutant strain increased the flux toward pentose phosphate pathway, which increased the supply of NADPH for enhanced lysine production. The present study highlights the importance of allosteric regulation on the flux control of central metabolism. The strategy described here can also be implemented to improve other oxaloacetate-derived products. PMID:24334667

  4. Loss of the proteostasis factor AIRAPL causes myeloid transformation by deregulating IGF-1 signaling.

    PubMed

    Osorio, Fernando G; Soria-Valles, Clara; Santiago-Fernández, Olaya; Bernal, Teresa; Mittelbrunn, María; Colado, Enrique; Rodríguez, Francisco; Bonzon-Kulichenko, Elena; Vázquez, Jesús; Porta-de-la-Riva, Montserrat; Cerón, Julián; Fueyo, Antonio; Li, Juan; Green, Anthony R; Freije, José M P; López-Otín, Carlos

    2016-01-01

    AIRAPL (arsenite-inducible RNA-associated protein-like) is an evolutionarily conserved regulator of cellular proteostasis linked to longevity in nematodes, but its biological function in mammals is unknown. We show herein that AIRAPL-deficient mice develop a fully-penetrant myeloproliferative neoplastic process. Proteomic analysis of AIRAPL-deficient mice revealed that this protein exerts its antineoplastic function through the regulation of the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. We demonstrate that AIRAPL interacts with newly synthesized insulin-related growth factor-1 receptor (IGF1R) polypeptides, promoting their ubiquitination and proteasome-mediated degradation. Accordingly, genetic and pharmacological IGF1R inhibitory strategies prevent the hematological disease found in AIRAPL-deficient mice as well as that in mice carrying the Jak2(V617F) mutation, thereby demonstrating the causal involvement of this pathway in the pathogenesis of myeloproliferative neoplasms. Consistent with its proposed role as a tumor suppressor of myeloid transformation, AIRAPL expression is widely abrogated in human myeloproliferative disorders. Collectively, these findings support the oncogenic relevance of proteostasis deregulation in hematopoietic cells, and they unveil novel therapeutic targets for these frequent hematological neoplasias.

  5. Genetic drivers of NF-κB deregulation in diffuse large B-cell lymphoma.

    PubMed

    Pasqualucci, Laura; Zhang, Baochun

    2016-08-01

    Diffuse large B cell lymphoma (DLBCL) is the most common form of B cell non-Hodgkin lymphoma worldwide and comprises a heterogeneous group of malignancies that originate from the malignant transformation of germinal center (GC) B cells. Over the past decade, significant improvement has been achieved in our understanding of the molecular pathogenesis underlying this disease, thanks in part to the implementation of powerful genomic technologies allowing genome-wide structural and functional analyses. These studies revealed the presence of multiple oncogenic alterations dysregulating signal transduction pathways that are normally required for the normal biology of the cells from which these tumors are derived. Among the pathways identified as recurrent targets of genetic lesions in DLBCL, NF-κB has emerged as a central player in the development and maintenance of this disease, particularly in the less curable, activated B cell (ABC)- like subtype. These lesions reveal vulnerabilities of the lymphoma cells that can be exploited for the design of more rationale therapeutic approaches. The purpose of this review is to summarize recent progresses in understanding the role of NF-κB deregulation in the pathogenesis of DLBCL, with emphasis on the genetic basis underlying its aberrant activation, in relationship to the normal biology of B lymphocytes, and the modelling of these lesions in the mouse. PMID:27546290

  6. The regulation and deregulation of Wnt signaling by PARK genes in health and disease

    PubMed Central

    Berwick, Daniel C.; Harvey, Kirsten

    2014-01-01

    Wingless/Int (Wnt) signaling pathways are signal transduction mechanisms that have been widely studied in the field of embryogenesis. Recent work has established a critical role for these pathways in brain development, especially of midbrain dopaminergic neurones. However, the fundamental importance of Wnt signaling for the normal function of mature neurones in the adult central nervous system has also lately been demonstrated by an increasing number of studies. Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide and is currently incurable. This debilitating disease is characterized by the progressive loss of a subset of midbrain dopaminergic neurones in the substantia nigra leading to typical extrapyramidal motor symptoms. The aetiology of PD is poorly understood but work performed over the last two decades has identified a growing number of genetic defects that underlie this condition. Here we review a growing body of data connecting genes implicated in PD—most notably the PARK genes—with Wnt signaling. These observations provide clues to the normal function of these proteins in healthy neurones and suggest that deregulated Wnt signaling might be a frequent pathomechanism leading to PD. These observations have implications for the pathogenesis and treatment of neurodegenerative diseases in general. PMID:24115276

  7. Truncated tau deregulates synaptic markers in rat model for human tauopathy

    PubMed Central

    Jadhav, Santosh; Katina, Stanislav; Kovac, Andrej; Kazmerova, Zuzana; Novak, Michal; Zilka, Norbert

    2015-01-01

    Synaptic failure and neurofibrillary degeneration are two major neuropathological substrates of cognitive dysfunction in Alzheimer’s disease (AD). Only a few studies have demonstrated a direct relationship between these two AD hallmarks. To investigate tau mediated synaptic injury we used rat model of tauopathy that develops extensive neurofibrillary pathology in the cortex. Using fractionation of cortical synapses, we identified an increase in endogenous rat tau isoforms in presynaptic compartment, and their mis-sorting to the postsynaptic density (PSD). Truncated transgenic tau was distributed in both compartments exhibiting specific phospho-pattern that was characteristic for each synaptic compartment. In the presynaptic compartment, truncated tau was associated with impairment of dynamic stability of microtubules which could be responsible for reduction of synaptic vesicles. In the PSD, truncated tau lowered the levels of neurofilaments. Truncated tau also significantly decreased the synaptic levels of Aβ40 but not Aβ42. These data show that truncated tau differentially deregulates synaptic proteome in pre- and postsynaptic compartments. Importantly, we show that alteration of Aβ can arise downstream of truncated tau pathology. PMID:25755633

  8. Deregulated expression of Cdc6 in the skin facilitates papilloma formation and affects the hair growth cycle.

    PubMed

    Búa, Sabela; Sotiropoulou, Peggy; Sgarlata, Cecilia; Borlado, Luis R; Eguren, Manuel; Domínguez, Orlando; Ortega, Sagrario; Malumbres, Marcos; Blanpain, Cedric; Méndez, Juan

    2015-01-01

    Cdc6 encodes a key protein for DNA replication, responsible for the recruitment of the MCM helicase to replication origins during the G1 phase of the cell division cycle. The oncogenic potential of deregulated Cdc6 expression has been inferred from cellular studies, but no mouse models have been described to study its effects in mammalian tissues. Here we report the generation of K5-Cdc6, a transgenic mouse strain in which Cdc6 expression is deregulated in tissues with stratified epithelia. Higher levels of CDC6 protein enhanced the loading of MCM complexes to DNA in epidermal keratinocytes, without affecting their proliferation rate or inducing DNA damage. While Cdc6 overexpression did not promote skin tumors, it facilitated the formation of papillomas in cooperation with mutagenic agents such as DMBA. In addition, the elevated levels of CDC6 protein in the skin extended the resting stage of the hair growth cycle, leading to better fur preservation in older mice.

  9. MEF2B mutations lead to deregulated expression of the BCL6 oncogene in Diffuse Large B cell Lymphoma

    PubMed Central

    Ying, Carol Y.; Dominguez-Sola, David; Fabi, Melissa; Lorenz, Ivo C.; Hussein, Shafinaz; Bansal, Mukesh; Califano, Andrea; Pasqualucci, Laura; Basso, Katia; Dalla-Favera, Riccardo

    2014-01-01

    The MEF2B gene encodes a transcriptional activator and is found mutated in ∼11% of diffuse large B cell lymphomas (DLBCLs) and ∼12% of follicular lymphomas. Here, we show that MEF2B directly activates the transcription of the proto-oncogene BCL6 in normal germinal-center B cells and is required for DLBCL proliferation. MEF2B mutations enhance MEF2B transcriptional activity either by disrupting its interaction with the co-repressor CABIN1, or by rendering it insensitive to phosphorylation- and sumoylation-mediated inhibitory signaling events. Consequently, Bcl-6 transcriptional activity is deregulated in DLBCL harboring MEF2B mutations. Thus, somatic mutations of MEF2B may contribute to lymphomagenesis by deregulating the expression of the BCL6 oncogene, and MEF2B may represent an alternative target to block Bcl-6 activity in DLBCLs. PMID:23974956

  10. [Effects of pharmacy market deregulation regarding patient-centred drug care in Germany from a health economics perspecitve].

    PubMed

    Rumm, R; Böcking, W

    2013-03-01

    This article analyses the impact of a potential deregulation Germany's pharmacy market by allowing foreign ownership of pharmacies and removing the limit of the number pharmacies that can be owned by a pharmacist. Based on a mathematical model and empirical values of foreign countries, scenarios for the German market are calculated and the impact on all participants of the health care system analysed. The key outcomes are:- A deregulation would enables the creation of pharmacy chains- In all simulated scenarios the total number of pharmacies would drastically grow- The increased pharmacy density improves patient centred drug care- The competition among pharmacies increases and leads to the closure of many independently owned and operated pharmacies.

  11. Advanced Gas Turbine (AGT) Technology Project

    NASA Technical Reports Server (NTRS)

    1984-01-01

    Technical work on the design and effort leading to the testing of a 74.5 kW (100 hp) automotive gas turbine engine is reviewed. Development of the engine compressor, gasifier turbine, power turbine, combustor, regenerator, and secondary system is discussed. Ceramic materials development and the application of such materials in the gas turbine engine components is described.

  12. Advanced Gas Turbine (AGT) powertrain system

    NASA Technical Reports Server (NTRS)

    Helms, H. E.; Kaufeld, J.; Kordes, R.

    1981-01-01

    A 74.5 kW(100 hp) advanced automotive gas turbine engine is described. A design iteration to improve the weight and production cost associated with the original concept is discussed. Major rig tests included 15 hours of compressor testing to 80% design speed and the results are presented. Approximately 150 hours of cold flow testing showed duct loss to be less than the design goal. Combustor test results are presented for initial checkout tests. Turbine design and rig fabrication is discussed. From a materials study of six methods to fabricate rotors, two have been selected for further effort. A discussion of all six methods is given.

  13. Advanced Gas Turbine (AGT) technology development

    NASA Technical Reports Server (NTRS)

    1983-01-01

    A 74.5 kW (100 hp) automotive gas turbine was evaluated. The engine structure, bearings, oil system, and electronics were demonstrated and no shaft dynamics or other vibration problem were encountered. Areas identified during the five tests are the scroll retention features, and transient thermal deflection of turbine backplates. Modifications were designed. Seroll retention is addressed by modifying the seal arrangement in front of the gasifier turbine assembly, which will increase the pressure load on the scroll in the forward direction and thereby increase the retention forces. the backplate thermal deflection is addressed by geometric changes and thermal insulation to reduce heat input. Combustor rig proof testing of two ceramic combustor assemblies was completed. The combustor was modified to incorporate slots and reduce sharp edges, which should reduce thermal stresses. The development work focused on techniques to sinter these barrier materials onto the ceramic rotors with successes for both material systems. Silicon carbide structural parts, including engine configuration gasifier rotors (ECRs), preliminary gasifier scroll parts, and gasifier and power turbine vanes are fabricated.

  14. Deregulation of a Hox Protein Regulatory Network Spanning Prostate Cancer Initiation and Progression

    PubMed Central

    Chen, James L.; Li, Jianrong; Kiriluk, Kyle J.; Rosen, Alex M.; Paner, Gladell P.; Antic, Tatjana; Lussier, Yves A.; Vander Griend, Donald J.

    2012-01-01

    Purpose The aberrant activity of developmental pathways in prostate cancer may provide significant insight into predicting tumor initiation and progression, as well as identifying novel therapeutic targets. To this end, despite shared androgen-dependence and functional similarities to the prostate gland, seminal vesicle cancer is exceptionally rare. Experimental Design We conducted genomic pathway analyses comparing patient-matched normal prostate and seminal vesicle epithelial cells to identify novel pathways for tumor initiation and progression. Derived gene expression profiles were grouped into cancer biomodules using a protein–protein network algorithm to analyze their relationship to known oncogenes. Each resultant biomodule was assayed for its prognostic ability against publically available prostate cancer patient gene array datasets. Results Analyses show that the embryonic developmental biomodule containing four homeobox gene family members (Meis1, Meis2, Pbx1, and HoxA9) detects a survival difference in a set of watchful-waiting patients (n = 172, P = 0.05), identify men who are more likely to recur biochemically postprostatectomy (n = 78, P = 0.02), correlate with Gleason score (r = 0.98, P = 0.02), and distinguish between normal prostate, primary tumor, and metastatic disease. In contrast to other cancer types, Meis1, Meis2, and Pbx1 expression is decreased in poor-prognosis tumors, implying that they function as tumor suppressor genes for prostate cancer. Immunohistochemical staining documents nuclear basal-epithelial and stromal Meis2 staining, with loss of Meis2 expression in prostate tumors. Conclusion These data implicate deregulation of the Hox protein cofactors Meis1, Meis2, and Pbx1 as serving a critical function to suppress prostate cancer initiation and progression. PMID:22723371

  15. Concordance of deregulated mechanisms unveiled in underpowered experiments: PTBP1 knockdown case study

    PubMed Central

    2014-01-01

    Background Genome-wide transcriptome profiling generated by microarray and RNA-Seq often provides deregulated genes or pathways applicable only to larger cohort. On the other hand, individualized interpretation of transcriptomes is increasely pursued to improve diagnosis, prognosis, and patient treatment processes. Yet, robust and accurate methods based on a single paired-sample remain an unmet challenge. Methods "N-of-1-pathways" translates gene expression data profiles into mechanism-level profiles on single pairs of samples (one p-value per geneset). It relies on three principles: i) statistical universe is a single paired sample, which serves as its own control; ii) statistics can be derived from multiple gene expression measures that share common biological mechanisms assimilated to genesets; iii) semantic similarity metric takes into account inter-mechanisms' relationships to better assess commonality and differences, within and cross study-samples (e.g. patients, cell-lines, tissues, etc.), which helps the interpretation of the underpinning biology. Results In the context of underpowered experiments, N-of-1-pathways predictions perform better or comparable to those of GSEA and Differentially Expressed Genes enrichment (DEG enrichment), within-and cross-datasets. N-of-1-pathways uncovered concordant PTBP1-dependent mechanisms across datasets (Odds-Ratios≥13, p-values≤1 × 10−5), such as RNA splicing and cell cycle. In addition, it unveils tissue-specific mechanisms of alternatively transcribed PTBP1-dependent genesets. Furthermore, we demonstrate that GSEA and DEG Enrichment preclude accurate analysis on single paired samples. Conclusions N-of-1-pathways enables robust and biologically relevant mechanism-level classifiers with small cohorts and one single paired samples that surpasses conventional methods. Further, it identifies unique sample/ patient mechanisms, a requirement for precision medicine. PMID:25079003

  16. Immune response and mitochondrial metabolism are commonly deregulated in DMD and aging skeletal muscle.

    PubMed

    Baron, Daniel; Magot, Armelle; Ramstein, Gérard; Steenman, Marja; Fayet, Guillemette; Chevalier, Catherine; Jourdon, Philippe; Houlgatte, Rémi; Savagner, Frédérique; Pereon, Yann

    2011-01-01

    Duchenne Muscular Dystrophy (DMD) is a complex process involving multiple pathways downstream of the primary genetic insult leading to fatal muscle degeneration. Aging muscle is a multifactorial neuromuscular process characterized by impaired muscle regeneration leading to progressive atrophy. We hypothesized that these chronic atrophying situations may share specific myogenic adaptative responses at transcriptional level according to tissue remodeling. Muscle biopsies from four young DMD and four AGED subjects were referred to a group of seven muscle biopsies from young subjects without any neuromuscular disorder and explored through a dedicated expression microarray. We identified 528 differentially expressed genes (out of 2,745 analyzed), of which 328 could be validated by an exhaustive meta-analysis of public microarray datasets referring to DMD and Aging in skeletal muscle. Among the 328 validated co-expressed genes, 50% had the same expression profile in both groups and corresponded to immune/fibrosis responses and mitochondrial metabolism. Generalizing these observed meta-signatures with large compendia of public datasets reinforced our results as they could be also identified in other pathological processes and in diverse physiological conditions. Focusing on the common gene signatures in these two atrophying conditions, we observed enrichment in motifs for candidate transcription factors that may coordinate either the immune/fibrosis responses (ETS1, IRF1, NF1) or the mitochondrial metabolism (ESRRA). Deregulation in their expression could be responsible, at least in part, for the same transcriptome changes initiating the chronic muscle atrophy. This study suggests that distinct pathophysiological processes may share common gene responses and pathways related to specific transcription factors.

  17. Epigenetic deregulation of Ellis Van Creveld confers robust Hedgehog signaling in adult T-cell leukemia.

    PubMed

    Takahashi, Ryutaro; Yamagishi, Makoto; Nakano, Kazumi; Yamochi, Toshiko; Yamochi, Tadanori; Fujikawa, Dai; Nakashima, Makoto; Tanaka, Yuetsu; Uchimaru, Kaoru; Utsunomiya, Atae; Watanabe, Toshiki

    2014-09-01

    One of the hallmarks of cancer, global gene expression alteration, is closely associated with the development and malignant characteristics associated with adult T-cell leukemia (ATL) as well as other cancers. Here, we show that aberrant overexpression of the Ellis Van Creveld (EVC) family is responsible for cellular Hedgehog (HH) activation, which provides the pro-survival ability of ATL cells. Using microarray, quantitative RT-PCR and immunohistochemistry we have demonstrated that EVC is significantly upregulated in ATL and human T-cell leukemia virus type I (HTLV-1)-infected cells. Epigenetic marks, including histone H3 acetylation and Lys4 trimethylation, are specifically accumulated at the EVC locus in ATL samples. The HTLV-1 Tax participates in the coordination of EVC expression in an epigenetic fashion. The treatment of shRNA targeting EVC, as well as the transcription factors for HH signaling, diminishes the HH activation and leads to apoptotic death in ATL cell lines. We also showed that a HH signaling inhibitor, GANT61, induces strong apoptosis in the established ATL cell lines and patient-derived primary ATL cells. Therefore, our data indicate that HH activation is involved in the regulation of leukemic cell survival. The epigenetically deregulated EVC appears to play an important role for HH activation. The possible use of EVC as a specific cell marker and a novel drug target for HTLV-1-infected T-cells is implicated by these findings. The HH inhibitors are suggested as drug candidates for ATL therapy. Our findings also suggest chromatin rearrangement associated with active histone markers in ATL.

  18. Expression of the Retrotransposon Helena Reveals a Complex Pattern of TE Deregulation in Drosophila Hybrids

    PubMed Central

    Romero-Soriano, Valèria; Garcia Guerreiro, Maria Pilar

    2016-01-01

    Transposable elements (TEs), repeated mobile sequences, are ubiquitous in the eukaryotic kingdom. Their mobilizing capacity confers on them a high mutagenic potential, which must be strongly regulated to guarantee genome stability. In the Drosophila germline, a small RNA-mediated silencing system, the piRNA (Piwi-interacting RNA) pathway, is the main responsible TE regulating mechanism, but some stressful conditions can destabilize it. For instance, during interspecific hybridization, genomic stress caused by the shock of two different genomes can lead, in both animals and plants, to higher transposition rates. A recent study in D. buzatii—D. koepferae hybrids detected mobilization of 28 TEs, yet little is known about the molecular mechanisms explaining this transposition release. We have characterized one of the mobilized TEs, the retrotransposon Helena, and used quantitative expression to assess whether its high transposition rates in hybrids are preceded by increased expression. We have also localized Helena expression in the gonads to see if cellular expression patterns have changed in the hybrids. To give more insight into changes in TE regulation in hybrids, we analysed Helena-specific piRNA populations of hybrids and parental species. Helena expression is not globally altered in somatic tissues, but male and female gonads have different patterns of deregulation. In testes, Helena is repressed in F1, increasing then its expression up to parental values. This is linked with a mislocation of Helena transcripts along with an increase of their specific piRNA levels. Ovaries have additive levels of Helena expression, but the ping-pong cycle efficiency seems to be reduced in F1 hybrids. This could be at the origin of new Helena insertions in hybrids, which would be transmitted to F1 hybrid female progeny. PMID:26812285

  19. Gene expression analysis in patients with traumatic anterior shoulder instability suggests deregulation of collagen genes.

    PubMed

    Belangero, Paulo Santoro; Leal, Mariana Ferreira; Figueiredo, Eduardo Antônio; Cohen, Carina; Pochini, Alberto de Castro; Smith, Marília Cardoso; Andreoli, Carlos Vicente; Belangero, Sintia Iole; Ejnisman, Benno; Cohen, Moises

    2014-10-01

    Shoulder dislocation occurs in 1-2% of the population. Capsular deformation is a key factor in shoulder dislocation; however, little is known about capsule biology. We evaluated, for the first time in literature, the expression of COL1A1, COL1A2, COL3A1 and COL5A1 in the antero-inferior, antero-superior and posterior regions of the glenohumeral capsule of 31 patients with anterior shoulder instability and eight controls. The expression of collagen genes was evaluated by quantitative reverse transcription-PCR. The expression of COL1A1, COL3A1 and the ratio of COL1A1/COL1A2 were increased in all three portions of the capsule in patients compared to controls (p < 0.05). COL1A2 expression was upregulated in the antero-superior and posterior sites of the capsule of patients (p < 0.05). The ratio of COL1A2/COL3A1 expression was reduced in capsule antero-inferior and posterior sites of patients compared to controls (p < 0.05). In the capsule antero-inferior site of patients, the ratios of COL1A1/COL5A1, CO1A2/COL5A1 and COL3A1/COL5A1 expression were increased (p < 0.05). In patients, COL1A1/COL5A1 was also increased in the posterior site (p < 0.05). We found deregulated expression of collagen genes across the capsule of shoulder instability patients. These molecular alterations may lead to modifications of collagen fibril structure and impairment of the healing process, possibly with a role in capsular deformation. PMID:25042113

  20. Deregulation of Ion Channel and Transporter Encoding Genes in Pediatric Gliomas

    PubMed Central

    Masselli, Marika; Laise, Pasquale; Tonini, Giulia; Fanelli, Duccio; Pillozzi, Serena; Cetica, Valentina; Da Ros, Martina; Sardi, Iacopo; Buccoliero, Anna Maria; Aricò, Maurizio; Genitori, Lorenzo; Becchetti, Andrea; Arcangeli, Annarosa

    2012-01-01

    Brain tumors, including the majority gliomas, are the leading cause of cancer-related death in children. World Health Organization has divided pediatric brain tumors into different grades and, based upon cDNA microarray data identifying gene expression profiles (GEPs), it has become evident in the last decade that the various grades involve different types of genetic alterations. However, it is not known whether ion channel and transporter genes, intimately involved in brain functioning, are associated with such GEPs. We determined the GEPs in an available cohort of 10 pediatric brain tumors initially by comparing the data obtained from four primary tumor samples and corresponding short-term cultures. The correspondence between the two types of samples was statistically significant. We then performed bioinformatic analyses on those samples (a total of nine) which corresponded to tumors of glial origin, either tissues or cell cultures, depending on the best “RNA integrity number.” We used R software to evaluate the genes which were differentially expressed (DE) in gliomas compared with normal brain. Applying a p-value below 0.01 and fold change ≥4, led to identification of 2284 DE genes. Through a Functional Annotation Analysis (FAA) using the NIH-DAVID software, the DE genes turned out to be associated mainly with: immune/inflammatory response, cell proliferation and survival, cell adhesion and motility, neuronal phenotype, and ion transport. We have shown that GEPs of pediatric brain tumors can be studied using either primary tumor samples or short-term cultures with similar results. From FAA, we concluded that, among DE genes, pediatric gliomas show a strong deregulation of genes related to ion channels and transporters. PMID:22662319

  1. Firm-stakeholder connectedness in the deregulating electric utility business: Exchange relationships in a network context

    NASA Astrophysics Data System (ADS)

    Heuer, Mark Alan

    2001-12-01

    This dissertation extends current research on firm-stakeholder relationships by proposing a stakeholder connectedness model in a network context involving the deregulating electric utility industry. Connectedness involves the degree to which firms and stakeholders form dependent-interdependent relationships in a network context. First, this dissertation suggests that firm-stakeholder relationships are multilateral and multidirectional. Evolving business practices increasingly involve models in which firms and stakeholders are connected through complex dependent-interdependent exchange relationships. Depending on the type of exchange involved, these relationships often are multilateral and multidirectional, particularly in a network context. Second, this dissertation presents a network-based model in which the degree of connectedness among firms and stakeholders are defined based on types of dependence-interdependence. Recognizing the social and economic nature of exchange among firms and stakeholders, this paper suggests that differing types of trust and control can effectively describe both dependence-interdependence and the degree of connectedness among firms and stakeholders. Third, this dissertation suggests that, from the perspective of exchange relationships in a network environment, power-based relationships provide only a partial explanation of firm-stakeholder interaction. This dissertation conceptualizes power as a subset of dependent-interdependent relationships and one of several factors that influence connectedness among firms and stakeholders in a network. The general proposition of this paper is that firms increasingly are interconnected through exchange relationships. Connectedness among firms and stakeholders in a network can be developed and maintained more effectively when based on long-term relationships. To support this proposition, models of differing types of firm-stakeholder connectedness are provided. Through case study research of firms

  2. Federal Agency and Federal Library Reports.

    ERIC Educational Resources Information Center

    Wooding, Janet E; Lisowski, Lori A.; Gilliam, Bo; Chute, Adrienne; Fischer, Audrey; Cole, John Y.; Tarr, Susan M.; Norris, Brian; Mehnert, Robert; Brandhorst, Ted; Sherman, Andrew M.; Willard, Robert S.

    1999-01-01

    Presents reports from: National Technical Information Service; National Archives and Records Administration; United States Information Agency; National Center for Educational Statistics Library Statistics Cooperative Program; Library of Congress; Center for the Book; Federal Library and Information Center Committee; National Agricultural Library;…

  3. Federal Agency and Federal Library Reports.

    ERIC Educational Resources Information Center

    Williams, Jane; And Others

    1994-01-01

    Includes reports from National Commission on Libraries and Information Science; National Technical Information Service; National Archives; United States Information Agency; National Center for Education Statistics; Library of Congress; Center for the Book; Federal Library and Information Center Committee; National Agricultural Library; National…

  4. Federal Agency and Federal Library Reports.

    ERIC Educational Resources Information Center

    Williams, Jane; Wooding, Janet E.; Lisowski, Lori A.; Borys, Cynthia; Chute, Adrienne; Fischer, Audrey; Cole, John Y.; Tarr, Susan M.; Norris, Brian; Mehnert, Robert; Brandhorst, Ted; Sherman, Andrew M.

    1998-01-01

    Contains reports from National Commission on Libraries and Information Science, National Technical Information Service, National Archives, U.S. Information Agency, National Center for Education Statistics, Library of Congress, Center for the Book, Federal Library and Information Center Committee, National Agricultural Library, National Library of…

  5. Federal Agency and Federal Library Reports.

    ERIC Educational Resources Information Center

    Vlach, Rosalie B.; Davis, Linda; Vecchiarelli, Marion H.; Fischer, Audrey; Cole, John Y.; Tarr, Susan M.; Carey, Len; Mehnert, Robert; Sherman, Andrew M.; Dunn, Christina

    2001-01-01

    Includes 11 reports from the National Commission on Libraries and Information Science; National Technical Information Service; National Archives and Records Administration; Library of Congress; Center for the Book; Federal Library and Information Center Committee; National Agricultural Library; National Library of Medicine; Government Printing…

  6. Navigating the new deregulated landscape: Opportunities and risks for wind energy

    SciTech Connect

    Fossum, D.J.; Hill, D.R.

    1997-12-31

    Major changes in the law governing the electric industry are underway, fundamentally altering how the generation and sale of electric power is regulated and how electric power is marketed in the United States. Legislative and regulatory initiatives promoting competition will create a variety of opportunities, and commensurate risks, for power generators, marketers, brokers, sellers, and purchasers. To succeed in the new marketplace, suppliers of renewable energy must understand the changes occurring on the state and federal levels, and position themselves to take advantage of the opportunities available. In this environment, monitoring and participating in state and federal legislative and regulatory efforts will be crucial for maximizing opportunities for wind energy.

  7. Deregulated expression of circadian clock and clock-controlled cell cycle genes in chronic lymphocytic leukemia.

    PubMed

    Rana, Sobia; Munawar, Mustafa; Shahid, Adeela; Malik, Meera; Ullah, Hafeez; Fatima, Warda; Mohsin, Shahida; Mahmood, Saqib

    2014-01-01

    Circadian rhythms are endogenous and self-sustained oscillations of multiple biological processes with approximately 24-h rhythmicity. Circadian genes and their protein products constitute the molecular components of the circadian oscillator that form positive/negative feedback loops and generate circadian rhythms. The circadian regulation extends from core clock genes to various clock-controlled genes that include various cell cycle genes. Aberrant expression of circadian clock genes, therefore, may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. The current study encompasses the investigation of simultaneous expression of four circadian clock genes (Bmal1, Clock, Per1 and Per2) and three clock-controlled cell cycle genes (Myc, Cyclin D1 and Wee1) at mRNA level and determination of serum melatonin levels in peripheral blood samples of 37 CLL (chronic lymphocytic leukemia) patients and equal number of age- and sex-matched healthy controls in order to indicate association between deregulated circadian clock and manifestation of CLL. Results showed significantly down-regulated expression of Bmal1, Per1, Per2 and Wee1 and significantly up-regulated expression of Myc and Cyclin D1 (P < 0.0001) in CLL patients as compared to healthy controls. When expression of these genes was compared between shift-workers and non-shift-workers within the CLL group, the expression was found more aberrant in shift-workers as compared to non-shift-workers. However, this difference was found statistically significant for Myc and Cyclin D1 only (P < 0.05). Serum melatonin levels were found significantly low (P < 0.0001) in CLL subjects as compared to healthy controls whereas melatonin levels were found still lower in shift-workers as compared to non-shift-workers within CLL group (P < 0.01). Our results suggest that aberrant expression of circadian clock genes can lead to aberrant expression of their downstream targets that are

  8. p16INK4A and p14ARF Tumor Suppressor Pathways Are Deregulated in Malignant Rhabdoid Tumors

    PubMed Central

    Venneti, Sriram; Le, Paul; Martinez, Daniel; Eaton, Katherine W.; Shyam, Nikhil; Jordan-Sciutto, Kelly L.; Pawel, Bruce; Biegel, Jaclyn A.; Judkins, Alexander R.

    2011-01-01

    Malignant rhabdoid tumors (MRT) are aggressive tumors associated with mutations in the SMARCB1 gene. In experimental systems, the loss of SMARCB1 is hypothesized to alter p16INK4A pathways resulting in repression of tumor suppressors. To determine whether these pathways are deregulated in human MRT, we used immunohistochemistry on tissue microarrays to evaluate p16INK4A/E2F1/RB and p14ARF/MDM2/p53 pathways in 25 atypical teratoid/ rhabdoid tumors (AT/RT) and 11 non-CNS MRT. p16INK4A was negative or showed focal weak expression. The p16INK4A downstream targets CDK4/cyclin D1/ppRB were variably expressed at moderate to low levels; E2F1 was negative. Unexpectedly, p14ARF expression was seen in many cases, which correlated positively with p53 and inversely with MDM2 immunostaining in AT/RT. TP53 mutational analysis in 19/25 AT/RT and 8/11 non-CNS MRT cases showed point mutations in only 3 AT/RT cases, suggesting that p53 expression was driven mainly by p14ARF. Finally, nucleophosmin, a protein that stabilizes p53, was positive in the majority of cases and colocalized with p53. Together, these data suggest that in MRT there is deregulation of not only p16INK4A, but also the p14ARF pathway. These results provide insights into cell cycle deregulation in the pathogenesis of human MRT and may aid in the design and evaluation of potential therapies for these tumors. PMID:21666498

  9. Competition and deregulation in the electric industry. A study of organizational change: The New York State Public Service Commission

    NASA Astrophysics Data System (ADS)

    Ashley, Deborah J. Cordaro

    2000-11-01

    Public organizations are formed in response to societal needs. They collect taxes, educate children, enforce laws and provide protection to the environment, the nation and consumers. One such organization is the New York State Public Service Commission. In 1907, legislation was passed to form the New York State Public Service Commission the first regulatory body of its kind in the United States. Its mission was to provide safe, reliable and reasonably priced electricity. Subsequently, this became the model that was implemented in every state in the nation. The past decade heralds an era of competition and a lessening of regulatory control. The telephone, natural gas and airline industries are in various stages of deregulation, and the electric industry is beginning down this path as well. In an environment such as this, are regulatory organizations necessary, and if they are, how can they organize to meet the new societal requirements? The case of the New York State Public Service Commission at this point in time offers a real time study of a regulatory body immersed in an environment that is calling for competition and an end to big government. Utilizing case studies of industries that have deregulated, or are in the process of deregulating, indicates a future societal need for regulations. This result does not lead to a conclusion that organizational change is unnecessary. This Dissertation will lay out the current organizational structure of the Public Service Commission, give an overview of the environmental signals, describe the mission/core values, and illustrate general political and employee factors that are indigenous to public service. Utilizing both classic and current organizational theory, an evaluation will be made of the Commission's need for change, their ability to change, and obstacles they may encounter.

  10. Stratifying risk of recurrence in stage II colorectal cancer using deregulated stromal and epithelial microRNAs.

    PubMed

    Bullock, Marc D; Pickard, Karen; Mitter, Richard; Sayan, A Emre; Primrose, John N; Ivan, Cristina; Calin, George A; Thomas, Gareth J; Packham, Graham K; Mirnezami, Alex H

    2015-03-30

    MicroRNAs (miRNAs) enable colonic epithelial cells to acquire malignant characteristics and metastatic capabilities. Recently, cancer relevant miRNAs deregulated during disease progression have also been identified in tumor-associated stroma.By combining laser-microdissection (LMD) with high-throughput screening and high-sensitivity quantitation techniques, miRNA expression in colorectal cancer (CRC) specimens and paired normal colonic tissue was independently characterized in stromal and epithelial tissue compartments. Notably, deregulation of the key oncogene miR-21 was identified exclusively as a stromal phenomenon and miR-106a, an epithelial phenomenon in the malignant state.MiRNAs identified in this study successfully distinguished CRC from normal tissue and metastatic from non-metastatic tumor specimens. Furthermore, in a separate cohort of 50 consecutive patients with CRC, stromal miR-21 and miR-556 and epithelial miR-106a expression predicted short disease free survival (DFS) and overall survival (OS) in stage II disease: miR-21 (DFS: HR = 2.68, p = 0.015; OS: HR = 2.47, p = 0.029); miR-556 (DFS: HR = 2.60, p = 0.018); miR-106a (DFS: HR = 2.91, p = 0.008; OS: HR = 2.25, p = 0.049); combined (All High vs. All Low. DFS: HR = 5.83, p = 0.002; OS: HR = 4.13, p = 0.007).These data support the notion that stromal as well as epithelial miRNAs play important roles during disease progression, and that mapping patterns of deregulated gene expression to the appropriate tumor strata may be a valuable aid to therapeutic decision making in CRC. PMID:25788261

  11. Deregulation of the Electric Industry and Its Potential Benefits for School Districts.

    ERIC Educational Resources Information Center

    Watkiss, Jeffrey D.

    1997-01-01

    The electric utility industry is the last bastion of regulated monopolies in the United States. An overview of recent competition in the electric-power industry at both the federal and state levels and how this may affect school districts is offered in this article. The text identifies and evaluates how school districts can obtain cheaper power…

  12. Federalism, Agenda Setting, and the Dynamics of Federal Education Policy.

    ERIC Educational Resources Information Center

    Manna, Paul

    This paper is part of a larger project on agenda setting in the U.S. federal system and the development of the federal education agenda since 1965. Two questions motivate the paper, one theoretical and the other empirical: (1) how does federalism affect the federal agenda?; and (2) what explains the development of federal involvement in K-12…

  13. Federal Internship Improvement Act

    THOMAS, 112th Congress

    Rep. Connolly, Gerald E. [D-VA-11

    2011-03-03

    03/18/2011 Referred to the Subcommittee on Federal Workforce, U.S. Postal Service, and Labor Policy. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

  14. Federal participation in LEED

    SciTech Connect

    Payne, Christopher; Dyer, Beverly

    2004-11-10

    The federal government has been an active participant in the development and use of USGBC's Leadership in Energy & Environmental Design Green Building Rating System (LEED). This paper presents a review of this participation and some expectations for ongoing partnership.

  15. State v. Federal Rights.

    ERIC Educational Resources Information Center

    Calpin, Joseph L.

    1991-01-01

    Presents a learning activity in which students compare their state constitution's bill of rights with the federal Bill of Rights. Provides a chart for identifying comparisons of enumerated rights. Includes background information and explains objectives and procedures. (CH)

  16. Mitochondrial DNA disturbances and deregulated expression of oxidative phosphorylation and mitochondrial fusion proteins in sporadic inclusion body myositis.

    PubMed

    Catalán-García, Marc; Garrabou, Glòria; Morén, Constanza; Guitart-Mampel, Mariona; Hernando, Adriana; Díaz-Ramos, Àngels; González-Casacuberta, Ingrid; Juárez, Diana-Luz; Bañó, Maria; Enrich-Bengoa, Jennifer; Emperador, Sonia; Milisenda, José César; Moreno, Pedro; Tobías, Ester; Zorzano, Antonio; Montoya, Julio; Cardellach, Francesc; Grau, Josep Maria

    2016-10-01

    Sporadic inclusion body myositis (sIBM) is one of the most common myopathies in elderly people. Mitochondrial abnormalities at the histological level are present in these patients. We hypothesize that mitochondrial dysfunction may play a role in disease aetiology. We took the following measurements of muscle and peripheral blood mononuclear cells (PBMCs) from 30 sIBM patients and 38 age- and gender-paired controls: mitochondrial DNA (mtDNA) deletions, amount of mtDNA and mtRNA, mitochondrial protein synthesis, mitochondrial respiratory chain (MRC) complex I and IV enzymatic activity, mitochondrial mass, oxidative stress and mitochondrial dynamics (mitofusin 2 and optic atrophy 1 levels). Depletion of mtDNA was present in muscle from sIBM patients and PBMCs showed deregulated expression of mitochondrial proteins in oxidative phosphorylation. MRC complex IV/citrate synthase activity was significantly decreased in both tissues and mitochondrial dynamics were affected in muscle. Depletion of mtDNA was significantly more severe in patients with mtDNA deletions, which also presented deregulation of mitochondrial fusion proteins. Imbalance in mitochondrial dynamics in muscle was associated with increased mitochondrial genetic disturbances (both depletion and deletions), demonstrating that proper mitochondrial turnover is essential for mitochondrial homoeostasis and muscle function in these patients.

  17. Deregulated expression of Cdc6 in the skin facilitates papilloma formation and affects the hair growth cycle.

    PubMed

    Búa, Sabela; Sotiropoulou, Peggy; Sgarlata, Cecilia; Borlado, Luis R; Eguren, Manuel; Domínguez, Orlando; Ortega, Sagrario; Malumbres, Marcos; Blanpain, Cedric; Méndez, Juan

    2015-01-01

    Cdc6 encodes a key protein for DNA replication, responsible for the recruitment of the MCM helicase to replication origins during the G1 phase of the cell division cycle. The oncogenic potential of deregulated Cdc6 expression has been inferred from cellular studies, but no mouse models have been described to study its effects in mammalian tissues. Here we report the generation of K5-Cdc6, a transgenic mouse strain in which Cdc6 expression is deregulated in tissues with stratified epithelia. Higher levels of CDC6 protein enhanced the loading of MCM complexes to DNA in epidermal keratinocytes, without affecting their proliferation rate or inducing DNA damage. While Cdc6 overexpression did not promote skin tumors, it facilitated the formation of papillomas in cooperation with mutagenic agents such as DMBA. In addition, the elevated levels of CDC6 protein in the skin extended the resting stage of the hair growth cycle, leading to better fur preservation in older mice. PMID:26697840

  18. Odontogenic Keratocysts Arise from Quiescent Epithelial Rests and Are Associated with Deregulated Hedgehog Signaling in Mice and Humans

    PubMed Central

    Grachtchouk, Marina; Liu, Jianhong; Wang, Aiqin; Wei, Lebing; Bichakjian, Christopher K.; Garlick, Jonathan; Paulino, Augusto F.; Giordano, Thomas; Dlugosz, Andrzej A.

    2006-01-01

    Odontogenic keratocysts in humans are aggressive, noninflammatory jaw cysts that may harbor PTCH1 mutations, leading to constitutive activity of the embryonic Hedgehog (Hh) signaling pathway. We show here that epithelial expression of the Hh transcriptional effector Gli2 is sufficient for highly penetrant keratocyst development in transgenic mice. Mouse and human keratocysts expressed similar markers, leading to tooth misalignment, bone remodeling, and craniofacial abnormalities. We detected Hh target gene expression in epithelial cells lining keratocysts from both species, implicating deregulated Hh signaling in their development. Most mouse keratocysts arose from rests of Malassez—quiescent, residual embryonic epithelial cells that remain embedded in the periodontal ligament surrounding mature teeth. In Gli2-expressing mice, these rests were stimulated to proliferate, stratify, and form a differentiated squamous epithelium. The frequent development of keratocysts in Gli2-expressing mice supports the idea that GLI transcription factor activity mediates pathological responses to deregulated Hh signaling in humans. Moreover, Gli2-mediated reactivation of quiescent epithelial rests to form keratocysts indicates that these cells retain the capacity to function as progenitor cells on activation by an appropriate developmental signal. PMID:16936257

  19. New Federalism, Taxes, and Cities.

    ERIC Educational Resources Information Center

    Kaplan, Marshall

    1982-01-01

    Discusses how recent changes in federal policies have adversely affected cities. Modifications of the state block grant system, tax laws, reductions in federal support for welfare programs, and a massive federal debt have all hurt urban economies. (AM)

  20. 76 FR 5787 - Federal Perkins Loan, Federal Work-Study, and Federal Supplemental Educational Opportunity Grant...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-02

    ... Federal Perkins Loan, Federal Work-Study, and Federal Supplemental Educational Opportunity Grant Programs... Perkins Loan, Federal Work-Study (FWS), and Federal Supplemental Educational Opportunity Grant (FSEOG.... The Work Colleges Program The Work Colleges September 30, Report of 2010-2011 award Program Report...

  1. 75 FR 12217 - Federal Perkins Loan, Federal Work-Study, and Federal Supplemental Educational Opportunity Grant...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-15

    ... Federal Perkins Loan, Federal Work-Study, and Federal Supplemental Educational Opportunity Grant programs... Perkins Loan, Federal Work-Study (FWS), and Federal Supplemental Educational Opportunity Grant (FSEOG... Administrator, 2020 Company, LLC, 3110 Fairview Park Drive, Suite 950, Falls Church, VA 22042. 3. The...

  2. Altered metabolic pathways in clear cell renal cell carcinoma: A meta-analysis and validation study focused on the deregulated genes and their associated networks

    PubMed Central

    Zaravinos, Apostolos; Pieri, Myrtani; Mourmouras, Nikos; Anastasiadou, Natassa; Zouvani, Ioanna; Delakas, Dimitris; Deltas, Constantinos

    2014-01-01

    Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal cell carcinoma (RCC). It is one of the most therapy-resistant carcinomas, responding very poorly or not at all to radiotherapy, hormonal therapy and chemotherapy. A more comprehensive understanding of the deregulated pathways in ccRCC can lead to the development of new therapies and prognostic markers. We performed a meta- analysis of 5 publicly available gene expression datasets and identified a list of co- deregulated genes, for which we performed extensive bioinformatic analysis coupled with experimental validation on the mRNA level. Gene ontology enrichment showed that many proteins are involved in response to hypoxia/oxygen levels and positive regulation of the VEGFR signaling pathway. KEGG analysis revealed that metabolic pathways are mostly altered in ccRCC. Similarly, Ingenuity Pathway Analysis showed that the antigen presentation, inositol metabolism, pentose phosphate, glycolysis/gluconeogenesis and fructose/mannose metabolism pathways are altered in the disease. Cellular growth, proliferation and carbohydrate metabolism, were among the top molecular and cellular functions of the co-deregulated genes. qRT-PCR validated the deregulated expression of several genes in Caki-2 and ACHN cell lines and in a cohort of ccRCC tissues. NNMT and NR3C1 increased expression was evident in ccRCC biopsies from patients using immunohistochemistry. ROC curves evaluated the diagnostic performance of the top deregulated genes in each dataset. We show that metabolic pathways are mostly deregulated in ccRCC and we highlight those being most responsible in its formation. We suggest that these genes are candidate predictive markers of the disease. PMID:25594006

  3. A Primer on Electric Utilities, Deregulation, and Restructuring of U.S. Electricity Markets

    SciTech Connect

    Warwick, William M.

    2002-06-03

    This primer is offered as an introduction to utility restructuring to better prepare readers for ongoing changes in public utilities and associated energy markets. It is written for use by individuals with responsibility for the management of facilities that use energy, including energy managers, procurement staff, and managers with responsibility for facility operations and budgets. The primer was prepared by the Pacific Northwest National Laboratory under sponsorship from the U.S. Department of Energy?s Federal Energy Management Program. The impetus for this primer originally came from the Government Services Administration who supported its initial development.

  4. Federalism and health policy.

    PubMed

    Nathan, Richard P

    2005-01-01

    This paper presents a cyclical theory of U.S. federalism and social policy: Many social policy initiatives are tested and refined at the state level, especially during conservative periods, and later morph into national policies. The paper describes such federalism cycles and offers an interpretation of why and how they occur, focusing on Medicaid. State activism has preserved and expanded Medicaid through policy innovation and resistance to retrenchment, especially in conservative periods, by taking advantage of the flexibility the program provides. I conclude that Medicaid's incremental/partnership approach is appropriate and feasible to build on for a future expansion of health care coverage.

  5. Federal water policy

    SciTech Connect

    Not Available

    1990-01-01

    The Federal Water Policy is a statement of the federal government's philosophy and goals for the nation's freshwater resources, and of the proposed ways of achieving them in cooperation with provincial governments. This document provides an overview of the policy, then presents details on the policy itself, the strategies for achievement of that policy, methods of applying it, and specific policy statements. These statements cover such topics as the management of toxic chemicals, water quality, ground water contamination, municipal water and sewer infrastructure, safe drinking water, wetlands preservation, hydroelectric development, navigation, native water rights, and Canada-US boundary management, among others.

  6. An integrated genome-wide approach to discover deregulated microRNAs in non-small cell lung cancer: Clinical significance of miR-23b-3p deregulation

    PubMed Central

    Begum, Shahnaz; Hayashi, Masamichi; Ogawa, Takenori; Jabboure, Fayez J.; Brait, Mariana; Izumchenko, Evgeny; Tabak, Sarit; Ahrendt, Steven A.; Westra, William H.; Koch, Wayne; Sidransky, David; Hoque, Mohammad O.

    2015-01-01

    In spite of significant technical advances, genesis and progression of non-small cell lung cancer (NSCLC) remain poorly understood. We undertook an integrated genetic approach to discover novel microRNAs that were deregulated in NSCLCs. A total 119 primary NSCLCs with matched normal were analyzed for genome-wide copy number changes. We also tested a subset of matched samples by microRNA expression array, and integrated them to identify microRNAs positioned in allelic imbalance area. Our findings support that most of the identified deregulated microRNAs (miR-21, miR-23b, miR-31, miR-126, miR-150, and miR-205) were positioned in allelic imbalance areas. Among microRNAs tested in independent 114 NSCLCs, overexpression of miR-23b was revealed to be a significantly poor prognostic factor of recurrence free survival (HR = 2.40, P = 0.005, 95%CI: 1.32–4.29) and overall survival (HR = 2.35, P = 0.005, 95%CI: 1.30–4.19) in multivariable analysis. In addition, overexpression of miR-23b in H1838 cell line significantly increased cell proliferation, while inhibition of miR-23b in H1437 and H1944 cell lines significantly decreased cell doubling time. In summary, integration of genomic analysis and microRNA expression profiling could identify novel cancer-related microRNAs, and miR-23b could be a potential prognostic marker for early stage NSCLCs. Further biological studies of miR-23b are warranted for the potential development of targeted therapy. PMID:26314549

  7. The Federal Library Committee.

    ERIC Educational Resources Information Center

    Robisheaux, Judy

    The history, goals, organization and achievements of the Federal Library Committee (FLC) are examined in this graduate paper. A brief initial section relates the history of the Committee from the first recognition of its necessity through its planning, official creation and establishment of responsibilities, organization and funding. The body of…

  8. Federal budget timetable

    NASA Astrophysics Data System (ADS)

    This is the federal budget timetable under the Balanced Budget and Emergency Deficit Control Act of 1985 (Gramm-Rudman-Hollings). These deadlines apply to fiscal years (FY) 1987-1991. The deficit reduction measures in Gramm-Rudman-Hollings would lead to a balanced budget in 1991.

  9. Federal Forecasters Directory, 1995.

    ERIC Educational Resources Information Center

    National Center for Education Statistics (ED), Washington, DC.

    This directory lists employees of the federal government who are involved in forecasting for policy formation and trend prediction purposes. Job title, agency, business address, phone or e-mail number, and specialty areas are listed for each employee. Employees are listed for the following agencies: (1) Bureau of the Census; (2) Bureau of Economic…

  10. Federal energy regulation

    SciTech Connect

    McKie, J.W.

    1984-01-01

    Federal energy policy since World War II has developed into a vast and multidirectional program of controls, incentives, restraints, and promotions. This development accelerated greatly during the critical decade after 1973, and has become a pervasive and sometimes controlling influence in the energy economy. Its purposes, responding to a multitude of interests and aims in the economy, have frequently been inconsistent, if not obscure, and the results have often been confusing or disappointing. This contribution considers the development and purposes of federal energy regulation during the last twenty years, especially since the ''''energy crisis'' of the early 1970s, and offers an appraisal of the successes and failures of several major federal regulatory programs. Whatever the motives and purposes that have actually guided the federal government in its intervention in the energy economy, economists and other critics may evaluate its programs according to whether or not they promote various ends that are deemed to be in the ''public interest.'' Regulation is often rationalized as an attempt to correct or compensate for a failure of the free, unregulated market to achieve some goal thought to be essential for good economic performance, or to fulfill other necessary public purposes.

  11. The Federal Deficit.

    ERIC Educational Resources Information Center

    Schug, Mark C., Ed.

    1986-01-01

    This first edition of a new semiannual publication for secondary school teachers of social studies features the article, "The Federal Deficit: Challenges and Opportunities for Policy Makers" (Walter Heller and Bruce Dalgaard) and provides ideas for subject area teaching activities in economics, U.S. government, and world history that offer…

  12. 76 FR 6759 - Monsanto Company and KWS SAAT AG; Decision With Respect to the Petition for Partial Deregulation...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-08

    ... Federal Register (75 FR 67945- 67946, Docket No. APHIS-2010-0047) announcing the availability of an... notice in the Federal Register (69 FR 61466-61467, Docket No. 04-075-1) announcing that the Monsanto/ KWS... published a notice in the Federal Register (70 FR 13007-13008, Docket No. 04-075-2) advising the public...

  13. Rural Education: The Federal Response.

    ERIC Educational Resources Information Center

    Hearn, Norman E.

    1981-01-01

    Reviews federal efforts to develop a rural education federal agenda, five basic problems of rural areas which lend themselves to federal solutions, Department of Education proposals for fiscal year 1982, significant federal responses/already in progress, and strengths and advantages of rural schools. (AN)

  14. An Oncogenic Role for Alternative NF-κB Signaling in DLBCL, Revealed Upon Deregulated BCL6 Expression

    PubMed Central

    Zhang, Baochun; Calado, Dinis Pedro; Wang, Zhe; Fröhler, Sebastian; Köchert, Karl; Qian, Yu; Koralov, Sergei B.; Schmidt-Supprian, Marc; Sasaki, Yoshiteru; Unitt, Christine; Rodig, Scott; Chen, Wei; Dalla-Favera, Riccardo; Alt, Frederick W.; Pasqualucci, Laura; Rajewsky, Klaus

    2015-01-01

    Diffuse large B cell lymphoma (DLBCL) is a complex disease comprising diverse subtypes and genetic profiles. Possibly due to the prevalence of genetic alterations activating canonical NF-κB activity, a role for oncogenic lesions that activate the alternative NF-κB pathway in DLBCL has remained elusive. Here we show that deletion/mutation of TRAF3, a negative regulator of the alternative NF-κB pathway, occurs in ∼15% of DLBCLs, and that it often coexists with BCL6 translocation, which prevents terminal B cell differentiation. Accordingly, in a mouse model constitutive activation of the alternative NF-κB pathway cooperates with BCL6 deregulation in DLBCL development. This work demonstrates a key oncogenic role for the alternative NF-κB pathway in DLBCL development. PMID:25921526

  15. Effects of ZnO nanoparticles in plants: Cytotoxicity, genotoxicity, deregulation of antioxidant defenses, and cell-cycle arrest.

    PubMed

    Ghosh, Manosij; Jana, Aditi; Sinha, Sonali; Jothiramajayam, Manivannan; Nag, Anish; Chakraborty, Anirban; Mukherjee, Amitava; Mukherjee, Anita

    2016-09-01

    Cytotoxicity, genotoxicity, and biochemical effects were evaluated in the plants Allium cepa, Nicotiana tabacum, and Vicia faba following exposure to ZnO nanoparticles (np; diameter, ∼85nm). In the root meristems of Allium cepa cells, we observed loss of membrane integrity, increased chromosome aberrations, micronucleus formation, DNA strand breaks, and cell-cycle arrest at the G2/M checkpoint. In Vicia faba and Nicotiana tabacum, we observed increased intracellular ROS production, lipid peroxidation, and activities of some antioxidant enzymes. TEM images revealed gross morphological alterations and internalization of the np. Our findings provide evidence of ZnO np toxicity, characterized by deregulation of components of ROS-antioxidant machinery, leading to DNA damage, cell-cycle arrest, and cell death. These plants, especially Allium cepa, are reliable systems for assessment of np toxicology. PMID:27542712

  16. Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer

    PubMed Central

    Frescas, David; Pagano, Michele

    2009-01-01

    The maintenance and preservation of distinct phases during the cell cycle is a highly complex and coordinated process. It is regulated by phosphorylation — through the activity of cyclin-dependent kinases (CDKs) — and protein degradation, which occurs through ubiquitin ligases such as SCF (SKP1–CUL1–F-box protein) complexes and APC/C (anaphase-promoting complex/cyclosome). Here, we explore the functionality and biology of the F-box proteins, SKP2 (S-phase kinase-associated protein 2) and β-TrCP (β-transducin repeat-containing protein), which are emerging as important players in cancer biogenesis owing to the deregulated proteolysis of their substrates. PMID:18500245

  17. KCa2 channels activation prevents [Ca2+]i deregulation and reduces neuronal death following glutamate toxicity and cerebral ischemia

    PubMed Central

    Dolga, A M; Terpolilli, N; Kepura, F; Nijholt, I M; Knaus, H-G; D'Orsi, B; Prehn, J H M; Eisel, U L M; Plant, T; Plesnila, N; Culmsee, C

    2011-01-01

    Exacerbated activation of glutamate receptor-coupled calcium channels and subsequent increase in intracellular calcium ([Ca2+]i) are established hallmarks of neuronal cell death in acute and chronic neurological diseases. Here we show that pathological [Ca2+]i deregulation occurring after glutamate receptor stimulation is effectively modulated by small conductance calcium-activated potassium (KCa2) channels. We found that neuronal excitotoxicity was associated with a rapid downregulation of KCa2.2 channels within 3 h after the onset of glutamate exposure. Activation of KCa2 channels preserved KCa2 expression and significantly reduced pathological increases in [Ca2+]i providing robust neuroprotection in vitro and in vivo. These data suggest a critical role for KCa2 channels in excitotoxic neuronal cell death and propose their activation as potential therapeutic strategy for the treatment of acute and chronic neurodegenerative disorders. PMID:21509037

  18. HDAC isoenzyme expression is deregulated in chronic lymphocytic leukemia B-cells and has a complex prognostic significance

    PubMed Central

    Van Damme, Michaël; Crompot, Emerence; Meuleman, Nathalie; Mineur, Philippe; Bron, Dominique; Lagneaux, Laurence; Stamatopoulos, Basile

    2012-01-01

    Histone deacetylases (HDACs) play a crucial role in chromatin structure and, consequently, gene expression. Their deregulation has been reported in various cancers. We performed a complete and comprehensive study of the expression of 18 HDACs (including Sirtuin; SIRT) by real-time PCR in a cohort of 200 chronic lymphocytic leukemia (CLL) patients with a median follow-up of 77 mo, and compared it with the results obtained from normal B cells. We also compared HDAC expression at diagnosis and after relapse. We observed significant deregulation (mostly upregulation) of HDACs in CLL. In terms of clinical significance, only HDAC6 was significantly correlated with treatment-free survival (TFS), whereas HDAC3 and SIRT2, 3 and 6 were correlated with overall survival (OS). A multivariate Cox regression stepwise analysis indicated that HDAC6, 7 and 10 and SIRT3 were TFS independent predictors. Interestingly, poor prognosis was associated with an overexpression of HDAC7 and 10 but an underexpression of HDAC6 and SIRT3. Therefore, these factors were combined in a TFS score: patients with a score of 0–1–2, 3 and 4 had a median TFS of 107, 57 and 26 mo, respectively (HR = 4.03, p < 0.0001). For OS, SIRT5 and 6 allowed stratification into 3 groups, with a median OS of > 360, 237 and 94 mo (HR = 6.38, p < 0.0001). However, we could not find statistical differences in HDAC expression after relapse. These results, validated by a 5-fold cross-validation, highlight the complex impact of HDAC expression in CLL clinical course. PMID:23108383

  19. Conserved region 3 of human papillomavirus 16 E7 contributes to deregulation of the retinoblastoma tumor suppressor.

    PubMed

    Todorovic, Biljana; Hung, Katherine; Massimi, Paola; Avvakumov, Nikita; Dick, Frederick A; Shaw, Gary S; Banks, Lawrence; Mymryk, Joe S

    2012-12-01

    The human papillomavirus (HPV) E7 oncoprotein binds cellular factors, preventing or retargeting their function and thereby making the infected cell conducive for viral replication. A key target of E7 is the product of the retinoblastoma susceptibility locus (pRb). This interaction results in the release of E2F transcription factors and drives the host cell into the S phase of the cell cycle. E7 binds pRb via a high-affinity binding site in conserved region 2 (CR2) and also targets a portion of cellular pRb for degradation via the proteasome. Evidence suggests that a secondary binding site exists in CR3, and that this interaction influences pRb deregulation. Additionally, evidence suggests that CR3 also participates in the degradation of pRb. We have systematically analyzed the molecular mechanisms by which CR3 contributes to deregulation of the pRb pathway by utilizing a comprehensive series of mutations in residues predicted to be exposed on the surface of HPV16 E7 CR3. Despite differences in the ability to interact with cullin 2, all CR3 mutants degrade pRb comparably to wild-type E7. We identified two specific patches of residues on the surface of CR3 that contribute to pRb binding independently of the high-affinity CR2 binding site. Mutants within CR3 that affect pRb binding are less effective than the wild-type E7 in overcoming pRb-induced cell cycle arrest. This demonstrates that the interaction between HPV16 E7 CR3 and pRb is functionally important for alteration of the cell cycle. PMID:23015707

  20. The influence of market deregulation on fast food consumption and body mass index: a cross-national time series analysis

    PubMed Central

    Kouvonen, Anne; Gimeno, David

    2014-01-01

    Abstract Objective To investigate the effect of fast food consumption on mean population body mass index (BMI) and explore the possible influence of market deregulation on fast food consumption and BMI. Methods The within-country association between fast food consumption and BMI in 25 high-income member countries of the Organisation for Economic Co-operation and Development between 1999 and 2008 was explored through multivariate panel regression models, after adjustment for per capita gross domestic product, urbanization, trade openness, lifestyle indicators and other covariates. The possible mediating effect of annual per capita intake of soft drinks, animal fats and total calories on the association between fast food consumption and BMI was also analysed. Two-stage least squares regression models were conducted, using economic freedom as an instrumental variable, to study the causal effect of fast food consumption on BMI. Findings After adjustment for covariates, each 1-unit increase in annual fast food transactions per capita was associated with an increase of 0.033 kg/m2 in age-standardized BMI (95% confidence interval, CI: 0.013–0.052). Only the intake of soft drinks – not animal fat or total calories – mediated the observed association (β: 0.030; 95% CI: 0.010–0.050). Economic freedom was an independent predictor of fast food consumption (β: 0.27; 95% CI: 0.16–0.37). When economic freedom was used as an instrumental variable, the association between fast food and BMI weakened but remained significant (β: 0.023; 95% CI: 0.001–0.045). Conclusion Fast food consumption is an independent predictor of mean BMI in high-income countries. Market deregulation policies may contribute to the obesity epidemic by facilitating the spread of fast food. PMID:24623903

  1. Microarray analysis of gene expression in vestibular schwannomas reveals SPP1/MET signaling pathway and androgen receptor deregulation

    PubMed Central

    TORRES-MARTIN, MIGUEL; LASSALETTA, LUIS; SAN-ROMAN-MONTERO, JESUS; DE CAMPOS, JOSE M.; ISLA, ALBERTO; GAVILAN, JAVIER; MELENDEZ, BARBARA; PINTO, GIOVANNY R.; BURBANO, ROMMEL R.; CASTRESANA, JAVIER S.; REY, JUAN A.

    2013-01-01

    Vestibular schwannomas are benign neoplasms that arise from the vestibular nerve. The hallmark of these tumors is the biallelic inactivation of neurofibromin 2 (NF2). Transcriptomic alterations, such as the neuregulin 1 (NRG1)/ErbB2 pathway, have been described in schwannomas. In this study, we performed a whole transcriptome analysis in 31 vestibular schwannomas and 9 control nerves in the Affymetrix Gene 1.0 ST platform, validated by quantitative real-time PCR (qRT-PCR) using TaqMan Low Density arrays. We performed a mutational analysis of NF2 by PCR/denaturing high-performance liquid chromatography (dHPLC) and multiplex ligation-dependent probe amplification (MLPA), as well as a microsatellite marker analysis of the loss of heterozygosity (LOH) of chromosome 22q. The microarray analysis demonstrated that 1,516 genes were deregulated and 48 of the genes were validated by qRT-PCR. At least 2 genetic hits (allelic loss and/or gene mutation) in NF2 were found in 16 tumors, seven cases showed 1 hit and 8 tumors showed no NF2 alteration. MET and associated genes, such as integrin, alpha 4 (ITGA4)/B6, PLEXNB3/SEMA5 and caveolin-1 (CAV1) showed a clear deregulation in vestibular schwannomas. In addition, androgen receptor (AR) downregulation may denote a hormonal effect or cause in this tumor. Furthermore, the osteopontin gene (SPP1), which is involved in merlin protein degradation, was upregulated, which suggests that this mechanism may also exert a pivotal role in schwannoma merlin depletion. Finally, no major differences were observed among tumors of different size, histological type or NF2 status, which suggests that, at the mRNA level, all schwannomas, regardless of their molecular and clinical characteristics, may share common features that can be used in their treatment. PMID:23354516

  2. miR-15/miR-16 loss, miR-21 upregulation, or deregulation of their target genes predicts poor prognosis in prostate cancer patients.

    PubMed

    Bonci, Désirée; De Maria, Ruggero

    2016-07-01

    It is clear that several prostate cancers remain indolent whereas others develop into advanced forms. There is a need to improve patient management by identifying biomarkers for personalized treatment. We demonstrated that miR-15/miR-16 loss, miR-21 upregulation, and deregulation of their target genes represent a promising predictive signature of poor patient prognosis. PMID:27652312

  3. Federalism and bioethics.

    PubMed

    Von Hagel, Alisa

    2014-01-01

    The absence of comprehensive federal oversight of human biotechnologies in the United States continues to stimulate academic discourse on the relative merits of European-style regulatory agencies as compared to the current, decentralized approach. Many American bioethicists support the latter, maintaining that the key features of federalism--policy experimentation and moral pluralism--allows for the efficient regulation of these complex and contentious issues. This paper examines state-level regulation of oocyte donation to assess claims regarding the superiority of this decentralized regulatory approach. Further, this paper introduces an additional element to this examination of state law, which concerns the degree to which the health and safety of key participants is addressed at the state level. This inquiry assesses one facet of fertility medicine and biomedical research law, oocyte donation, an analysis that can be used to inform the broader discourse regarding the regulation of human biotechnologies and bioethical issues by the states.

  4. Needle Federated Search Engine

    SciTech Connect

    2009-12-01

    The Idaho National Laboratory (INL) has combined a number of technologies, tools, and resources to accomplish a new means of federating search results. The resulting product is a search engine called Needle, an open-source-based tool that the INL uses internally for researching across a wide variety of information repositories. Needle has a flexible search interface that allows end users to point at any available data source. A user can select multiple sources such as commercial databases (Web of Science, Engineering Index), external resources (WorldCat, Google Scholar), and internal corporate resources (email, document management system, library collections) in a single interface with one search query. In the future, INL hopes to offer this open-source engine to the public. This session will outline the development processes for making Needle™s search interface and simplifying the federation of internal and external data sources.

  5. Needle Federated Search Engine

    2009-12-01

    The Idaho National Laboratory (INL) has combined a number of technologies, tools, and resources to accomplish a new means of federating search results. The resulting product is a search engine called Needle, an open-source-based tool that the INL uses internally for researching across a wide variety of information repositories. Needle has a flexible search interface that allows end users to point at any available data source. A user can select multiple sources such as commercialmore » databases (Web of Science, Engineering Index), external resources (WorldCat, Google Scholar), and internal corporate resources (email, document management system, library collections) in a single interface with one search query. In the future, INL hopes to offer this open-source engine to the public. This session will outline the development processes for making Needle™s search interface and simplifying the federation of internal and external data sources.« less

  6. Federal Interagency Geothermal Activities

    SciTech Connect

    Anderson, Arlene; Prencipe, Loretta; Todaro, Richard M.; Cuyler, David; Eide, Elizabeth

    2011-06-01

    This collaborative document describes the roles and responsibilities of key Federal agencies in the development of geothermal technologies including the U.S. Department of Energy (DOE); the U.S. Department of Agriculture (USDA), including the U.S. Forest Service; the U.S. Department of Interior (DOI), including the United States Geological Survey (USGS) and Bureau of Land Management (BLM); the Environmental Protection Agency (EPA); and the Department of Defense (DOD).

  7. Federating Metadata Catalogs

    NASA Astrophysics Data System (ADS)

    Baru, C.; Lin, K.

    2009-04-01

    The Geosciences Network project (www.geongrid.org) has been developing cyberinfrastructure for data sharing in the Earth Science community based on a service-oriented architecture. The project defines a standard "software stack", which includes a standardized set of software modules and corresponding service interfaces. The system employs Grid certificates for distributed user authentication. The GEON Portal provides online access to these services via a set of portlets. This service-oriented approach has enabled the GEON network to easily expand to new sites and deploy the same infrastructure in new projects. To facilitate interoperation with other distributed geoinformatics environments, service standards are being defined and implemented for catalog services and federated search across distributed catalogs. The need arises because there may be multiple metadata catalogs in a distributed system, for example, for each institution, agency, geographic region, and/or country. Ideally, a geoinformatics user should be able to search across all such catalogs by making a single search request. In this paper, we describe our implementation for such a search capability across federated metadata catalogs in the GEON service-oriented architecture. The GEON catalog can be searched using spatial, temporal, and other metadata-based search criteria. The search can be invoked as a Web service and, thus, can be imbedded in any software application. The need for federated catalogs in GEON arises because, (i) GEON collaborators at the University of Hyderabad, India have deployed their own catalog, as part of the iGEON-India effort, to register information about local resources for broader access across the network, (ii) GEON collaborators in the GEO Grid (Global Earth Observations Grid) project at AIST, Japan have implemented a catalog for their ASTER data products, and (iii) we have recently deployed a search service to access all data products from the EarthScope project in the US

  8. Cream-skimming in deregulated social health insurance: evidence from Switzerland.

    PubMed

    Beck, K; Zweifel, P

    1998-01-01

    Policymakers fear that health insurers when exposed to competition will engage in cream-skimming (i.e. selection of good risks) rather than trying to improve their benefit to premium ratio. This fear surfaced also when Swiss federal government proposed pro-competitive Law on social health insurance, which barely passed a popular referendum in 1994. While a risk equalization mechanism based on age, gender, and place of residence has already been created, there is a considerable interest in improving its formula. This paper shows that a dummy variable indicating an individual's death during the period of observation causes the coefficient of determination to jump from 0.039 to 0.111. More-over, simulations of the risk selection process suggest that risk equalization should be made a permanent institution rather than being limited to a life of 10 years as prescribed by present legislation. In fact, the formula in use, with all its shortcomings, can be shown to neutralize to a great extent insurer interest in cream skimming provided he takes a longer-run view.

  9. An Xrootd Italian Federation

    NASA Astrophysics Data System (ADS)

    Boccali, T.; Donvito, G.; Diacono, D.; Marzulli, G.; Pompili, A.; Della Ricca, G.; Mazzoni, E.; Argiro, S.; Gregori, D.; Grandi, C.; Bonacorsi, D.; Lista, L.; Fabozzi, F.; Barone, L. M.; Santocchia, A.; Riahi, H.; Tricomi, A.; Sgaravatto, M.; Maron, G.

    2014-06-01

    The Italian community in CMS has built a geographically distributed network in which all the data stored in the Italian region are available to all the users for their everyday work. This activity involves at different level all the CMS centers: the Tier1 at CNAF, all the four Tier2s (Bari, Rome, Legnaro and Pisa), and few Tier3s (Trieste, Perugia, Torino, Catania, Napoli, ...). The federation uses the new network connections as provided by GARR, our NREN (National Research and Education Network), which provides a minimum of 10 Gbit/s to all the sites via the GARR-X[2] project. The federation is currently based on Xrootd[1] technology, and on a Redirector aimed to seamlessly connect all the sites, giving the logical view of a single entity. A special configuration has been put in place for the Tier1, CNAF, where ad-hoc Xrootd changes have been implemented in order to protect the tape system from excessive stress, by not allowing WAN connections to access tape only files, on a file-by-file basis. In order to improve the overall performance while reading files, both in terms of bandwidth and latency, a hierarchy of xrootd redirectors has been implemented. The solution implemented provides a dedicated Redirector where all the INFN sites are registered, without considering their status (T1, T2, or T3 sites). An interesting use case were able to cover via the federation are disk-less Tier3s. The caching solution allows to operate a local storage with minimal human intervention: transfers are automatically done on a single file basis, and the cache is maintained operational by automatic removal of old files.

  10. Assisted Living Federation of America

    MedlinePlus

    ... Logos Membership FAQs Advocacy Advocacy Top Trending Issues Silver PAC Federal Public Policy State Regulations and Licensing ... Argentum Member Pledge Advocacy Advocacy Top Trending Issues Silver PAC Argentum Advocates Cobb Cup Federal Public Policy ...

  11. Characteristics of the Federal Executive.

    ERIC Educational Resources Information Center

    Civil Service Commission, Washington, DC.

    The personal characteristics, educational background, occupations, and attitudes of 54 Federal Executives who attended Session IX of the Federal Executive Institute, U. S. Civil Service Commission, are given. The average age of the group was 47.6 years (range 36 to 61). The federal grades were 18% in GS-5, 66% in GS-16 and equivalent, and 16% in…

  12. The Federal Air Pollution Program.

    ERIC Educational Resources Information Center

    National Air Pollution Control Administration (DHEW), Washington, DC.

    Described is the Federal air pollution program as it was in 1967. The booklet is divided into these major topics: History of the Federal Program; Research; Assistance to State and Local Governments; Abatement and Prevention of Air Pollution; Control of Motor Vehicle Pollution; Information and Education; and Conclusion. Federal legislation has…

  13. Science in the Federal Government.

    ERIC Educational Resources Information Center

    Thibodeau, Sharon Gibbs

    1985-01-01

    Examines the realm of science and the federal government made evident in the 1950s by A. Hunter Dupree's classic work on the subject. Federal science before 1940, federal science since 1940, and sources of historical materials are among the major areas considered. (JN)

  14. 78 FR 29353 - Federal Need Analysis Methodology for the 2014-15 Award Year-Federal Pell Grant, Federal Perkins...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-20

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF EDUCATION Federal Need Analysis Methodology for the 2014-15 Award Year-- Federal Pell Grant, Federal Perkins Loan, Federal Work-Study, Federal Supplemental Educational Opportunity Grant, William D. Ford Federal...

  15. 75 FR 62365 - Monsanto Company and KWS SAAT AG; Supplemental Request for Partial Deregulation of Roundup Ready...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-08

    ... October 19, 2004, APHIS published a notice in the Federal Register (69 FR 61466-61467, Docket No. 04-075-1... Register on March 17, 2005 (70 FR 13007-13008, Docket No. 04-075-2), advising the public of our... preparing an EIS, for which we published a notice \\1\\ in the Federal Register (75 FR 29969-29972, Docket...

  16. Multiple myeloma–related deregulation of bone marrow–derived CD34+ hematopoietic stem and progenitor cells

    PubMed Central

    Cadeddu, Ron-Patrick; Brueckmann, Ines; Fröbel, Julia; Geyh, Stefanie; Büst, Sebastian; Fischer, Johannes C.; Roels, Frederik; Wilk, Christian Matthias; Schildberg, Frank A.; Hünerlitürkoglu, Ali-Nuri; Zilkens, Christoph; Jäger, Marcus; Steidl, Ulrich; Zohren, Fabian; Fenk, Roland; Kobbe, Guido; Brors, Benedict; Czibere, Akos; Schroeder, Thomas; Trumpp, Andreas; Haas, Rainer

    2012-01-01

    Multiple myeloma (MM) is a clonal plasma cell disorder frequently accompanied by hematopoietic impairment. We show that hematopoietic stem and progenitor cells (HSPCs), in particular megakaryocyte-erythrocyte progenitors, are diminished in the BM of MM patients. Genomic profiling of HSPC subsets revealed deregulations of signaling cascades, most notably TGFβ signaling, and pathways involved in cytoskeletal organization, migration, adhesion, and cell-cycle regulation in the patients. Functionally, proliferation, colony formation, and long-term self-renewal were impaired as a consequence of activated TGFβ signaling. In accordance, TGFβ levels in the BM extracellular fluid were elevated and mesenchymal stromal cells (MSCs) had a reduced capacity to support long-term hematopoiesis of HSPCs that completely recovered on blockade of TGFβ signaling. Furthermore, we found defective actin assembly and down-regulation of the adhesion receptor CD44 in MM HSPCs functionally reflected by impaired migration and adhesion. Still, transplantation into myeloma-free NOG mice revealed even enhanced engraftment and normal differentiation capacities of MM HSPCs, which underlines that functional impairment of HSPCs depends on MM-related microenvironmental cues and is reversible. Taken together, these data implicate that hematopoietic suppression in MM emerges from the HSPCs as a result of MM-related microenvironmental alterations. PMID:22517906

  17. Enhancer sequence variants and transcription-factor deregulation synergize to construct pathogenic regulatory circuits in B-cell lymphoma.

    PubMed

    Koues, Olivia I; Kowalewski, Rodney A; Chang, Li-Wei; Pyfrom, Sarah C; Schmidt, Jennifer A; Luo, Hong; Sandoval, Luis E; Hughes, Tyler B; Bednarski, Jeffrey J; Cashen, Amanda F; Payton, Jacqueline E; Oltz, Eugene M

    2015-01-20

    Most B-cell lymphomas arise in the germinal center (GC), where humoral immune responses evolve from potentially oncogenic cycles of mutation, proliferation, and clonal selection. Although lymphoma gene expression diverges significantly from GC B cells, underlying mechanisms that alter the activities of corresponding regulatory elements (REs) remain elusive. Here we define the complete pathogenic circuitry of human follicular lymphoma (FL), which activates or decommissions REs from normal GC B cells and commandeers enhancers from other lineages. Moreover, independent sets of transcription factors, whose expression was deregulated in FL, targeted commandeered versus decommissioned REs. Our approach revealed two distinct subtypes of low-grade FL, whose pathogenic circuitries resembled GC B or activated B cells. FL-altered enhancers also were enriched for sequence variants, including somatic mutations, which disrupt transcription-factor binding and expression of circuit-linked genes. Thus, the pathogenic regulatory circuitry of FL reveals distinct genetic and epigenetic etiologies for GC B-cell transformation.

  18. Biofluid metabotyping of occupationally exposed subjects to air pollution demonstrates high oxidative stress and deregulated amino acid metabolism

    PubMed Central

    Pradhan, Surya Narayan; Das, Aleena; Meena, Ramovatar; Nanda, Ranjan Kumar; Rajamani, Paulraj

    2016-01-01

    Occupational exposure to air pollution induces oxidative stress and prolonged exposure increases susceptibility to cardiovascular and respiratory diseases in several working groups. Biofluid of these subjects may reflect perturbed metabolic phenotypes. In this study we carried out a comparative molecular profiling study using parallel biofluids collected from subjects (n = 85) belonging to auto rickshaw drivers (ARD), traffic cops (TC) and office workers (OW). Higher levels of oxidative stress and inflammation markers in serum of ARD subjects were observed as compared to OW and TC. Uni and multivariate analyses of metabolites identified in urine by 1H NMR revealed 11 deregulated molecules in ARD subjects and involved in phenylalanine, histidine, arginine and proline metabolism. Despite contribution of confounding factors like exposure period, dietary factors including smoking and alcohol status, our results demonstrate existence of exposure specific metabotypes in biofluids of ARD, OW and TC groups. Monitoring serum oxidative stress and inflammation markers and urine metabolites by NMR may be useful to characterize perturbed metabolic phenotypes in populations exposed to urban traffic air pollution. PMID:27767182

  19. SLIT2 attenuation during lung cancer progression deregulates beta-catenin and E-cadherin and associates with poor prognosis.

    PubMed

    Tseng, Ruo-Chia; Lee, Shih-Hua; Hsu, Han-Shui; Chen, Ben-Han; Tsai, Wan-Ching; Tzao, Ching; Wang, Yi-Ching

    2010-01-15

    Chromosome 4p15.3 is frequently deleted in late-stage lung cancer. We investigated the significance of the SLIT2 gene located in this region to lung cancer progression. SLIT2 encodes an extracellular glycoprotein that can suppress breast cancer by regulating beta-catenin. In this study, we examined alterations in the structure or expression of SLIT2, its receptor ROBO1, and beta-catenin, along with the AKT/glycogen synthase kinase 3beta (GSK3beta)/beta-transducin repeat-containing protein (betaTrCP) pathway in lung cancer cell lines and patients. Low SLIT2 expression correlated with an upward trend of pathological stage and poorer survival in lung cancer patients. Importantly, SLIT2, betaTrCP, and beta-catenin expression levels predicted postoperative recurrence of lung cancer in patients. Stimulating SLIT2 expression by various methods increased the level of E-cadherin caused by attenuation of its transcriptional repressor SNAI1. Conversely, knocking down SLIT2 expression increased cell migration and reduced cell adhesion through coordinated deregulation of beta-catenin and E-cadherin/SNAI1 in the AKT/GSK3beta/betaTrCP pathway. Our findings indicate that SLIT2 suppresses lung cancer progression, defining it as a novel "theranostic" factor with potential as a therapeutic target and prognostic predictor in lung cancer. Cancer Res; 70(2); 543-51.

  20. Importance of Maternal Diabetes on the Chronological Deregulation of the Intrauterine Development: An Experimental Study in Rat

    PubMed Central

    Salazar García, Marcela; Reyes Maldonado, Elba; Revilla Monsalve, María Cristina; Villavicencio Guzmán, Laura; Reyes López, Alfonso; Sánchez-Gómez, Concepción

    2015-01-01

    We investigated whether maternal diabetes induced in rats using streptozotocin (STZ) on Day 5 of pregnancy affects the intrauterine developmental timeline. A total of 30 pregnant Sprague-Dawley diabetic rats (DRs) and 20 control rats (CRs) were used to obtain 21-day fetuses (F21) and newborn (NB) pups. Gestational age, weight, and body size were recorded as were the maxillofacial morphometry and morphohistological characteristics of the limbs. In DRs, pregnancy continued for ∼1.7 days, and delivery occurred 23 days postcoitus (DPC). In this group, the number of pups was lower, and 13% had maxillofacial defects. F21 in the DR group had lower weights and were smaller; moreover, the morphological characteristics of the maxillofacial structures, derived from the neural crest, were discordant with their chronological gestational age, resembling 18- to 19-day-old fetuses. These deficiencies were counterbalanced in NB pups. We conclude that hyperglycemia, which results from maternal diabetes and precedes embryo implantation, deregulates the intrauterine developmental timeline, restricts embryo-fetal growth, and primarily delays the remodeling and maturation of the structures derived from neural crest cells. PMID:25756053

  1. Maternal exposure to di-(2-ethylhexyl) phthalate exposure deregulates blood pressure, adiposity, cholesterol metabolism and social interaction in mouse offspring.

    PubMed

    Lee, Kuan-I; Chiang, Chin-Wei; Lin, Hui-Ching; Zhao, Jin-Feng; Li, Cheng-Ta; Shyue, Song-Kun; Lee, Tzong-Shyuan

    2016-05-01

    Long-term exposure to di-(2-ethylhexyl) phthalate (DEHP) is highly associated with carcinogenicity, fetotoxicity, psychological disorders and metabolic diseases, but the detrimental effects and mechanisms are not fully understood. We investigated the effect of exposing mouse mothers to DEHP, and the underlying mechanism, on blood pressure, obesity and cholesterol metabolism as well as psychological and learning behaviors in offspring. Tail-cuff plethysmography was used for blood pressure measurement; Western blot used was for phosphorylation and expression of protein; hematoxylin and eosin staining, Nissl staining and Golgi staining were used for histological examination. The serum levels of cholesterol, triglycerides and glucose were measured by blood biochemical analysis. Hepatic cholesterol and triglyceride levels were assessed by colorimetric assay kits. Offspring behaviors were evaluated by open-field activity, elevated plus maze, social preference test and Morris water maze. Maternal DEHP exposure deregulated the phosphorylation of endothelial nitric oxide synthase and upregulated angiotensin type 1 receptor in offspring, which led to increased blood pressure. It led to obesity in offspring by increasing the size of adipocytes in white adipose tissue and number of adipocytes in brown adipose tissue. It increased the serum level of cholesterol in offspring by decreasing the hepatic capacity for cholesterol clearance. The impaired social interaction ability induced by maternal DEHP exposure might be due to abnormal neuronal development. Collectively, our findings provide new evidence that maternal exposure to DEHP has a lasting effect on the physiological functions of the vascular system, adipose tissue and nerve system in offspring.

  2. IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation.

    PubMed

    Oktay, Yavuz; Ülgen, Ege; Can, Özge; Akyerli, Cemaliye B; Yüksel, Şirin; Erdemgil, Yiğit; Durası, I Melis; Henegariu, Octavian Ioan; Nanni, E Paolo; Selevsek, Nathalie; Grossmann, Jonas; Erson-Omay, E Zeynep; Bai, Hanwen; Gupta, Manu; Lee, William; Turcan, Şevin; Özpınar, Aysel; Huse, Jason T; Sav, M Aydın; Flanagan, Adrienne; Günel, Murat; Sezerman, O Uğur; Yakıcıer, M Cengiz; Pamir, M Necmettin; Özduman, Koray

    2016-01-01

    The single nucleotide polymorphism rs55705857, located in a non-coding but evolutionarily conserved region at 8q24.21, is strongly associated with IDH-mutant glioma development and was suggested to be a causal variant. However, the molecular mechanism underlying this association has remained unknown. With a case control study in 285 gliomas, 316 healthy controls, 380 systemic cancers, 31 other CNS-tumors, and 120 IDH-mutant cartilaginous tumors, we identified that the association was specific to IDH-mutant gliomas. Odds-ratios were 9.25 (5.17-16.52; 95% CI) for IDH-mutated gliomas and 12.85 (5.94-27.83; 95% CI) for IDH-mutated, 1p/19q co-deleted gliomas. Decreasing strength with increasing anaplasia implied a modulatory effect. No somatic mutations were noted at this locus in 114 blood-tumor pairs, nor was there a copy number difference between risk-allele and only-ancestral allele carriers. CCDC26 RNA-expression was rare and not different between the two groups. There were only minor subtype-specific differences in common glioma driver genes. RNA sequencing and LC-MS/MS comparisons pointed to significantly altered MYC-signaling. Baseline enhancer activity of the conserved region specifically on the MYC promoter and its further positive modulation by the SNP risk-allele was shown in vitro. Our findings implicate MYC deregulation as the underlying cause of the observed association. PMID:27282637

  3. Haploinsufficiency of RPS14 in 5q− syndrome is associated with deregulation of ribosomal- and translation-related genes

    PubMed Central

    Pellagatti, Andrea; Hellström-Lindberg, Eva; Giagounidis, Aristoteles; Perry, Janet; Malcovati, Luca; Della Porta, Matteo G; Jädersten, Martin; Killick, Sally; Fidler, Carrie; Cazzola, Mario; Wainscoat, James S; Boultwood, Jacqueline

    2008-01-01

    We have previously demonstrated haploinsufficiency of the ribosomal gene RPS14, which is required for the maturation of 40S ribosomal subunits and maps to the commonly deleted region, in the 5q− syndrome. Patients with Diamond-Blackfan anaemia (DBA) show haploinsufficiency of the closely related ribosomal protein RPS19, and show a consequent downregulation of multiple ribosomal- and translation-related genes. By analogy with DBA, we have investigated the expression profiles of a large group of ribosomal- and translation-related genes in the CD34+ cells of 15 myelodysplastic syndrome (MDS) patients with 5q− syndrome, 18 MDS patients with refractory anaemia (RA) and a normal karyotype, and 17 healthy controls. In this three-way comparison, 55 of 579 ribosomal- and translation-related probe sets were found to be significantly differentially expressed, with approximately 90% of these showing lower expression levels in the 5q− syndrome patient group. Using hierarchical clustering, patients with the 5q− syndrome could be separated both from other patients with RA and healthy controls solely on the basis of the deregulated expression of ribosomal- and translation-related genes. Patients with the 5q− syndrome have a defect in the expression of genes involved in ribosome biogenesis and in the control of translation, suggesting that the 5q− syndrome represents a disorder of aberrant ribosome biogenesis. PMID:18477045

  4. Phosphoprotein network analysis of white adipose tissues unveils deregulated pathways in response to high-fat diet

    PubMed Central

    Asfa, Alli Shaik; Qiu, Beiying; Wee, Sheena; Choi, Hyungwon; Gunaratne, Jayantha; Tergaonkar, Vinay

    2016-01-01

    Despite efforts in the last decade, signaling aberrations associated with obesity remain poorly understood. To dissect molecular mechanisms that define this complex metabolic disorder, we carried out global phosphoproteomic analysis of white adipose tissue (WAT) from mice fed on low-fat diet (LFD) and high-fat diet (HFD). We quantified phosphorylation levels on 7696 peptides, and found significant differential phosphorylation levels in 282 phosphosites from 191 proteins, including various insulin-responsive proteins and metabolic enzymes involved in lipid homeostasis in response to high-fat feeding. Kinase-substrate prediction and integrated network analysis of the altered phosphoproteins revealed underlying signaling modulations during HFD-induced obesity, and suggested deregulation of lipogenic and lipolytic pathways. Mutation of the differentially-regulated novel phosphosite on cytoplasmic acetyl-coA forming enzyme ACSS2 (S263A) upon HFD-induced obesity led to accumulation of serum triglycerides and reduced insulin-responsive AKT phosphorylation as compared to wild type ACSS2, thus highlighting its role in obesity. Altogether, our study presents a comprehensive map of adipose tissue phosphoproteome in obesity and reveals many previously unknown candidate phosphorylation sites for future functional investigation. PMID:27180971

  5. New Methodology for Evaluating Optimal Pricing for Primary Regulation of Deregulated Power Systems under Steady State Condition

    NASA Astrophysics Data System (ADS)

    Satyaramesh, P. V.; RadhaKrishna, C.

    2013-06-01

    A generalized pricing structure for procurement of power under frequency ancillary service is developed in this paper. It is a frequency linked-price model and suitable for deregulation market environment. This model takes into consideration: governor characteristics and frequency characteristics of generator as additional parameters in load flow method. The main objective of the new approach proposed in this paper is to establish bidding price structure for frequency regulation services in competitive ancillary electrical markets under steady state condition. Lot of literatures are available for calculating the frequency deviations with respect to load changes by using dynamic simulation methods. But in this paper, the model computes the frequency deviations for additional requirements of power under steady state with considering power system network topology. An attempt is also made in this paper to develop optimal bidding price structure for the frequency-regulated systems. It gives a signal to traders or bidders that the power demand can be assessed more accurately much closer to real time and helps participants bid more accurate quantities on day-ahead market. The recent trends of frequency linked-price model existing in Indian power systems issues required for attention are also dealt in this paper. Test calculations have been performed on 30-bus system. The paper also explains adoptability of 33 this model to practical Indian power system. The results presented are analyzed and useful conclusions are drawn.

  6. Deregulation in STAT signaling is important for cutaneous T-cell lymphoma (CTCL) pathogenesis and cancer progression.

    PubMed

    Netchiporouk, Elena; Litvinov, Ivan V; Moreau, Linda; Gilbert, Martin; Sasseville, Denis; Duvic, Madeleine

    2014-01-01

    Deregulation of STAT signaling has been implicated in the pathogenesis for a variety of cancers, including CTCL. Constitutive activation of STAT5 and STAT3 was observed in early and late stages of CTCL, respectively. In early stages, IL-2, IL-7 and IL-15 signaling via JAK1 and JAK3 kinases is believed to be responsible for activating STAT5, while in advanced stages development of IL-21 autocrine signaling is thought to be important for STAT3 activation. Recent molecular evidence further suggests that upregulation of STAT5 in early disease stages results in increased expression of oncogenic miR-155 microRNA that subsequently targets STAT4 expression on mRNA level. STAT4 signaling is known to be critical for T helper (Th) 1 phenotype differentiation and its loss results in a switch from Th1 to Th2 phenotype in malignant T cells. During this switch the expression of STAT6 is often upregulated in CTCL. In advanced stages, activation of STAT3 and STAT5 may become completely cytokine-independent and be driven only via constitutively active JAK1 and JAK3 kinases. Further research into the molecular pathogenesis of JAK/STAT signaling in this cancer may enable us to develop effective therapies for our patients. PMID:25485578

  7. Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia.

    PubMed

    Irvine, David A; Zhang, Bin; Kinstrie, Ross; Tarafdar, Anuradha; Morrison, Heather; Campbell, Victoria L; Moka, Hothri A; Ho, Yinwei; Nixon, Colin; Manley, Paul W; Wheadon, Helen; Goodlad, John R; Holyoake, Tessa L; Bhatia, Ravi; Copland, Mhairi

    2016-01-01

    Targeting the Hedgehog (Hh) pathway represents a potential leukaemia stem cell (LSC)-directed therapy which may compliment tyrosine kinase inhibitors (TKIs) to eradicate LSC in chronic phase (CP) chronic myeloid leukaemia (CML). We set out to elucidate the role of Hh signaling in CP-CML and determine if inhibition of Hh signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC. Assessment of Hh pathway gene and protein expression demonstrated that the Hh pathway is activated in CD34(+) CP-CML stem/progenitor cells. LDE225 (Sonidegib), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with nilotinib, inhibited the Hh pathway in CD34(+) CP-CML cells, reducing the number and self-renewal capacity of CML LSC in vitro. The combination had no effect on normal haemopoietic stem cells. When combined, LDE225 + nilotinib reduced CD34(+) CP-CML cell engraftment in NSG mice and, upon administration to EGFP(+) /SCLtTA/TRE-BCR-ABL mice, the combination enhanced survival with reduced leukaemia development in secondary transplant recipients. In conclusion, the Hh pathway is deregulated in CML stem and progenitor cells. We identify Hh pathway inhibition, in combination with nilotinib, as a potentially effective therapeutic strategy to improve responses in CP-CML by targeting both stem and progenitor cells. PMID:27157927

  8. Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia

    PubMed Central

    Irvine, David A.; Zhang, Bin; Kinstrie, Ross; Tarafdar, Anuradha; Morrison, Heather; Campbell, Victoria L.; Moka, Hothri A.; Ho, Yinwei; Nixon, Colin; Manley, Paul W.; Wheadon, Helen; Goodlad, John R.; Holyoake, Tessa L.; Bhatia, Ravi; Copland, Mhairi

    2016-01-01

    Targeting the Hedgehog (Hh) pathway represents a potential leukaemia stem cell (LSC)-directed therapy which may compliment tyrosine kinase inhibitors (TKIs) to eradicate LSC in chronic phase (CP) chronic myeloid leukaemia (CML). We set out to elucidate the role of Hh signaling in CP-CML and determine if inhibition of Hh signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC. Assessment of Hh pathway gene and protein expression demonstrated that the Hh pathway is activated in CD34+ CP-CML stem/progenitor cells. LDE225 (Sonidegib), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with nilotinib, inhibited the Hh pathway in CD34+ CP-CML cells, reducing the number and self-renewal capacity of CML LSC in vitro. The combination had no effect on normal haemopoietic stem cells. When combined, LDE225 + nilotinib reduced CD34+ CP-CML cell engraftment in NSG mice and, upon administration to EGFP+ /SCLtTA/TRE-BCR-ABL mice, the combination enhanced survival with reduced leukaemia development in secondary transplant recipients. In conclusion, the Hh pathway is deregulated in CML stem and progenitor cells. We identify Hh pathway inhibition, in combination with nilotinib, as a potentially effective therapeutic strategy to improve responses in CP-CML by targeting both stem and progenitor cells. PMID:27157927

  9. Chromatin remodelers HELLS and UHRF1 mediate the epigenetic deregulation of genes that drive retinoblastoma tumor progression

    PubMed Central

    Benavente, Claudia A.; Finkelstein, David; Johnson, Dianna A.; Marine, Jean-Christophe; Ashery-Padan, Ruth; Dyer, Michael A.

    2014-01-01

    The retinoblastoma (Rb) family of proteins are key regulators of cell cycle exit during development and their deregulation is associated with cancer. Rb is critical for normal retinal development and germline mutations lead to retinoblastoma making retinae an attractive system to study Rb family signaling. Rb coordinates proliferation and differentiation through the E2f family of transcription factors, a critical interaction for the role of Rb in retinal development and tumorigenesis. However, whether the roles of the different E2fs are interchangeable in controlling development and tumorigenesis in the retina or if they have selective functions remains unknown. In this study, we found that E2f family members play distinct roles in the development and tumorigenesis. In Rb;p107-deficient retinae, E2f1 and E2f3 inactivation rescued tumor formation but only E2f1 rescued the retinal development phenotype. This allowed the identification of key target genes for Rb/E2f family signaling contributing to tumorigenesis and those contributing to developmental defects. We found that Sox4 and Sox11 genes contribute to the developmental phenotype and Hells and Uhrf1 contribute to tumorigenesis. Using orthotopic human xenografts, we validated that upregulation of HELLS and UHRF1 is essential for the tumor phenotype. Also, these epigenetic regulators are important for the regulation of SYK. PMID:25338120

  10. Expression deregulation of mir31 and CXCL12 in two types of oral precancers and cancer: importance in progression of precancer and cancer

    NASA Astrophysics Data System (ADS)

    Chattopadhyay, Esita; Singh, Richa; Ray, Anindita; Roy, Roshni; de Sarkar, Navonil; Paul, Ranjan Rashmi; Pal, Mousumi; Aich, Ritesh; Roy, Bidyut

    2016-09-01

    Oral cancer generally progresses from precancerous lesions such as leukoplakia (LK), lichen planus (LP) and oral submucous fibrosis (OSMF). Since few of these precancers progress to cancers; it is worth to identify biological molecules that may play important roles in progression. Here, expression deregulation of 7 miRNAs (mir204, mir31, mir31*, mir133a, mir7, mir206 and mir1293) and their possible target genes in 23 cancers, 18 LK, 12 LP, 23 OSMF tissues compared to 20 healthy tissues was determined by qPCR method. Expression of mir7, mir31, mir31* and mir1293 was upregulated and that of mir133a, mir204 and mir206 was downregulated in cancer. Expression of most of these miRNAs was also upregulated in LK and LP tissues but not in OSMF. Expression deregulation of some of the target genes was also determined in cancer, LK and LP tissues. Significant upregulation of mir31 and downregulation of its target gene, CXCL12, in cancer, LK and LP tissues suggest their importance in progression of precancer to cancer. Expression upregulation of mir31 was also validated using GEO data sets. Although sample size is low, novelty of this work lies in studying expression deregulation of miRNAs and target genes in oral cancer and three types of precancerous lesions.

  11. Expression deregulation of mir31 and CXCL12 in two types of oral precancers and cancer: importance in progression of precancer and cancer

    PubMed Central

    Chattopadhyay, Esita; Singh, Richa; Ray, Anindita; Roy, Roshni; De Sarkar, Navonil; Paul, Ranjan Rashmi; Pal, Mousumi; Aich, Ritesh; Roy, Bidyut

    2016-01-01

    Oral cancer generally progresses from precancerous lesions such as leukoplakia (LK), lichen planus (LP) and oral submucous fibrosis (OSMF). Since few of these precancers progress to cancers; it is worth to identify biological molecules that may play important roles in progression. Here, expression deregulation of 7 miRNAs (mir204, mir31, mir31*, mir133a, mir7, mir206 and mir1293) and their possible target genes in 23 cancers, 18 LK, 12 LP, 23 OSMF tissues compared to 20 healthy tissues was determined by qPCR method. Expression of mir7, mir31, mir31* and mir1293 was upregulated and that of mir133a, mir204 and mir206 was downregulated in cancer. Expression of most of these miRNAs was also upregulated in LK and LP tissues but not in OSMF. Expression deregulation of some of the target genes was also determined in cancer, LK and LP tissues. Significant upregulation of mir31 and downregulation of its target gene, CXCL12, in cancer, LK and LP tissues suggest their importance in progression of precancer to cancer. Expression upregulation of mir31 was also validated using GEO data sets. Although sample size is low, novelty of this work lies in studying expression deregulation of miRNAs and target genes in oral cancer and three types of precancerous lesions. PMID:27597234

  12. Deregulation Impact in Negotiating a New Electrical Contract Between NASA Glenn Research Center at Lewis Field and FirstEnergy Corp., Cleveland, Ohio, USA

    NASA Technical Reports Server (NTRS)

    Quach, Quyen T.; Zala, Laszlo F.

    2002-01-01

    The governor of the State of Ohio signed amended substitute Senate bill 3 on July 6, 1999, requiring Ohio's electric industry to change from a monopoly environment to a competitive electric environment for generation services. The start date for competitive retail generation services was set for January 1, 2001. This new deregulation law allowed all Ohioans to choose the supplier of generation service, but the transmission and distribution would remain regulated. It also required electric utilities to unbundle the three main components (generation, transmission, and distribution) and make other changes designed to produce a competitive electric generation market. While deregulation was taking shape, the NASA Glenn Research Center electrical contract with FirstEnergy Corp. of Cleveland, Ohio, was to expire on September 7, 1999. Glenn strategically evaluated and incorporated the impacts of electric deregulation in the negotiations. Glenn and FirstEnergy spent over a year in negotiations until the Glenn utility team and the FirstEnergy negotiating team came to an agreement in the fall of 2000, and a new contract became effective on January 1, 2001.

  13. Global Profiling in Vestibular Schwannomas Shows Critical Deregulation of MicroRNAs and Upregulation in Those Included in Chromosomal Region 14q32

    PubMed Central

    Torres-Martin, Miguel; Lassaletta, Luis; de Campos, Jose M.; Isla, Alberto; Gavilan, Javier; Pinto, Giovanny R.; Burbano, Rommel R.; Latif, Farida; Melendez, Barbara; Castresana, Javier S.; Rey, Juan A.

    2013-01-01

    Background Vestibular schwannomas are benign tumors that arise from Schwann cells in the VIII cranial pair and usually present NF2 gene mutations and/or loss of heterozygosity on chromosome 22q. Deregulation has also been found in several genes, such as ERBB2 and NRG1. MicroRNAs are non-coding RNAs approximately 21 to 23 nucleotides in length that regulate mRNAs, usually by degradation at the post-transcriptional level. Methods We used microarray technology to test the deregulation of miRNAs and other non-coding RNAs present in GeneChip miRNA 1.0 (Affymetrix) over 16 vestibular schwannomas and 3 control-nerves, validating 10 of them by qRT-PCR. Findings Our results showed the deregulation of 174 miRNAs, including miR-10b, miR-206, miR-183 and miR-204, and the upregulation of miR-431, miR-221, miR-21 and miR-720, among others. The results also showed an aberrant expression of other non-coding RNAs. We also found a general upregulation of the miRNA cluster located at chromosome 14q32. Conclusion Our results suggest that several miRNAs are involved in tumor formation and/or maintenance and that global upregulation of the 14q32 chromosomal site contains miRNAs that may represent a therapeutic target for this neoplasm. PMID:23776562

  14. Expression deregulation of mir31 and CXCL12 in two types of oral precancers and cancer: importance in progression of precancer and cancer.

    PubMed

    Chattopadhyay, Esita; Singh, Richa; Ray, Anindita; Roy, Roshni; De Sarkar, Navonil; Paul, Ranjan Rashmi; Pal, Mousumi; Aich, Ritesh; Roy, Bidyut

    2016-01-01

    Oral cancer generally progresses from precancerous lesions such as leukoplakia (LK), lichen planus (LP) and oral submucous fibrosis (OSMF). Since few of these precancers progress to cancers; it is worth to identify biological molecules that may play important roles in progression. Here, expression deregulation of 7 miRNAs (mir204, mir31, mir31*, mir133a, mir7, mir206 and mir1293) and their possible target genes in 23 cancers, 18 LK, 12 LP, 23 OSMF tissues compared to 20 healthy tissues was determined by qPCR method. Expression of mir7, mir31, mir31* and mir1293 was upregulated and that of mir133a, mir204 and mir206 was downregulated in cancer. Expression of most of these miRNAs was also upregulated in LK and LP tissues but not in OSMF. Expression deregulation of some of the target genes was also determined in cancer, LK and LP tissues. Significant upregulation of mir31 and downregulation of its target gene, CXCL12, in cancer, LK and LP tissues suggest their importance in progression of precancer to cancer. Expression upregulation of mir31 was also validated using GEO data sets. Although sample size is low, novelty of this work lies in studying expression deregulation of miRNAs and target genes in oral cancer and three types of precancerous lesions. PMID:27597234

  15. The impossible dream? How Nuclear Electric, Ltd. pulled itself out of the ashes of government ownership and became highly competitive in a privatized and deregulating British power market

    SciTech Connect

    Maycock, P.

    1998-12-31

    The day was dark for Nuclear Electric plc. when the British government decided it would privatize and deregulate the electric utility industry. For years, Nuclear Electric and other UK-based fossil power producers had been operating in a regulated market where the state set and guaranteed the price of electricity. All that was changing in Britain as the government introduced competition and as customers looked forward to purchasing power from the lowest bidder. Essentially the situation in England was much the same as it is now in the US: there was major momentum toward deregulation. The reality of competition in Britain came as good news to many power producers--in particular those who kept the lights on cost effectively. Others, However, weren`t so optimistic, especially nuclear plants that traditionally bear higher safety and maintenance costs than their fossil counterparts. Taking its cues from the City (Britain`s Wall Street), the British government simply considered nuclear generators to be unreliable, high cost, unprofitable organizations incapable of surviving in a privatized environment. It therefore left its nuclear power plants off the docket when selling (privatizing) its generating capacity. This paper describes how Nuclear Electric Ltd. became competitive in a deregulated environment.

  16. Federal Ocean Energy Technology

    NASA Astrophysics Data System (ADS)

    1987-10-01

    The Department of Energy's (DOE) Ocean Energy Technology (OET) Program is looking for cost-effective ways to harness ocean energy to help power tomorrow's world. Federally sponsored researchers are studying methods to transform the solar heat stored in the ocean's surface waters into electricity as well as new ways to convert wave energy into mechanical energy or electricity. This report provides a summary of research completed during FY86. Four major research areas are addressed in the work covered by this report: Thermodynamic Research and Analysis addresses the process and system analyses which provide the underlying understanding of physical effects which constitute the energy conversion processes, Experimental Verification and Testing provides confirmation of the analytical projections and empirical relationships, Materials and Structural Research addresses special materials compatibility issues related to operation in the sea. Much of its focus is on concepts for the system CWP which is a major technology cost driver, and Oceanographic, Environmental, and Geotechnical Research addresss those unique design requirements imposed by construction in steep slope coastal areas.

  17. Federal Environmental Permitting Handbook

    SciTech Connect

    Not Available

    1991-05-01

    The handbook consists of eight chapters addressing permitting and licensing requirements under the Resource Conservation and Recovery Act (RCRA), the Comprehensive Environmental Response, Compensation, and Liability Act of 1980, as amended by the Superfund Amendments and Reauthorization Act of 1986 (CERCLA/SARA), the Atomic Energy Act (AEA), the Clean Air Act (CAA), the Clean Water Act (CWA), the Federal Insectide, Fungicide, and Rodenticide Act (FIFRA), the Safe Drinking Water Act (SDWA), and the Toxic Substances Control Act (TSCA). Each chapter consists of: (1) an introduction to the statute and permitting requirements; (2) a diagram illustrating the relationship between permitting requirements under the statute being discussed and permitting requirements from other environmental statutes which may have to be addressed when applying for a particular permit (e.g., when applying for a RCRA permit, permits and permit applications under the CWA, CAA, SDWA, etc. would have to be listed in the RCRA permit application); and, (3) a compilation of the permitting requirements for the regulatory program resulting from the statute. In addition, the Handbook contains a permitting keyword index and a listing of hotline telephone numbers for each of the statutes.

  18. Federal Buildings Supplemental Survey 1993

    SciTech Connect

    1995-11-01

    The Energy Information Administration (EIA) of the US Department of Energy (DOE) is mandated by Congress to be the agency that collects, analyzes, and disseminates impartial, comprehensive data about energy including the volume consumed, its customers, and the purposes for which it is used. The Federal Buildings Supplemental Survey (FBSS) was conducted by EIA in conjunction with DOE`s Office of Federal Energy Management Programs (OFEMP) to gain a better understanding of how Federal buildings use energy. This report presents the data from 881 completed telephone interviews with Federal buildings in three Federal regions. These buildings were systematically selected using OFEMP`s specifications; therefore, these data do not statistically represent all Federal buildings in the country. The purpose of the FBSS was threefold: (1) to understand the characteristics of Federal buildings and their energy use; (2) to provide a baseline in these three Federal regions to measure future energy use in Federal buildings as required in EPACT; and (3) to compare building characteristics and energy use with the data collected in the CBECS.

  19. 41 CFR 102-79.40 - Can Federal agencies allot space in Federal buildings to Federal credit unions?

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... allot space in Federal buildings to Federal credit unions? 102-79.40 Section 102-79.40 Public Contracts... REGULATION REAL PROPERTY 79-ASSIGNMENT AND UTILIZATION OF SPACE Assignment and Utilization of Space Federal Credit Unions § 102-79.40 Can Federal agencies allot space in Federal buildings to Federal credit...

  20. 41 CFR 102-79.40 - Can Federal agencies allot space in Federal buildings to Federal credit unions?

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... allot space in Federal buildings to Federal credit unions? 102-79.40 Section 102-79.40 Public Contracts... REGULATION REAL PROPERTY 79-ASSIGNMENT AND UTILIZATION OF SPACE Assignment and Utilization of Space Federal Credit Unions § 102-79.40 Can Federal agencies allot space in Federal buildings to Federal credit...

  1. 41 CFR 102-79.40 - Can Federal agencies allot space in Federal buildings to Federal credit unions?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... allot space in Federal buildings to Federal credit unions? 102-79.40 Section 102-79.40 Public Contracts... REGULATION REAL PROPERTY 79-ASSIGNMENT AND UTILIZATION OF SPACE Assignment and Utilization of Space Federal Credit Unions § 102-79.40 Can Federal agencies allot space in Federal buildings to Federal credit...

  2. Helping Federal Policymakers Understand and Support Data Literacy. Federal Spotlight

    ERIC Educational Resources Information Center

    Data Quality Campaign, 2014

    2014-01-01

    Current federal and state policies focus on improved results for students through quality teaching. Strategies in school improvement plans, data-driven teacher evaluation, assessments and rigorous standards, competency-based learning, and innovative digital platforms make teacher data use essential. While state and federal policies are asking…

  3. Emissions markets, power markets and market power: A study of the interactions between contemporary emissions markets and deregulated electricity markets

    NASA Astrophysics Data System (ADS)

    Dormady, Noah Christopher

    Chapter 1: A Monte Carlo Approach. The use of auctions to distribute tradeable property rights to firms in already heavily concentrated markets may further exacerbate the problems of market power that exist within those markets. This chapter provides a model of a two-stage emissions market modeled after a contemporary regional permit trading market in the United States, the Regional Greenhouse Gas Initiative, Inc. (RGGI). It then introduces Oligopsony 1.0, a C# software package constructed in the .NET environment that simulates uniform-price auctions using stochastic Monte Carlo simulation for modeling market power in tradeable property rights auctions. Monte Carlo methods add a probabilistic element to standard auction theoretic equilibria. The results of these simulations indicate that there can be significant non-linearities between profit and market power as exercised through strategic demand reduction. This analysis finds the optimum point of strategic demand reduction that enables the firm to exploit these non-linearities, and it determines the probability distributions of these optima using kernel density analysis. Chapter 2: An Experimental Approach. How will emerging auction-based emissions markets function within the context of today's deregulated auction-based electricity markets? This chapter provides an experimental analysis of a joint energy-emissions market. The impact of market power and collusion among dominant firms is evaluated to determine the extent to which an auction-based tradeable permit market influences performance in an adjacent electricity market. The experimental treatment design controls for a variety of real-world institutional features, including variable demand, permit banking, inter-temporal (multi-round) dynamics, a tightening cap, and resale. Results suggest that the exercise of market power significantly increases electricity auction clearing prices, without significantly increasing emissions

  4. 78 FR 41183 - Federal Aviation Administration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-09

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF TRANSPORTATION Federal Aviation Administration Meeting: RTCA Program Management Committee AGENCY: Federal Aviation.... Paige Williams, Management Analyst, NextGen, Business Operations Group, Federal Aviation...

  5. Altered expression of the imprinted transcription factor PLAGL1 deregulates a network of genes in the human IUGR placenta.

    PubMed

    Iglesias-Platas, Isabel; Martin-Trujillo, Alex; Petazzi, Paolo; Guillaumet-Adkins, Amy; Esteller, Manel; Monk, David

    2014-12-01

    Genomic imprinting is the epigenetic process that results in monoallelic expression of genes depending on parental origin. These genes are known to be critical for placental development and fetal growth in mammals. Aberrant epigenetic profiles at imprinted loci, such as DNA methylation defects, are surprisingly rare in pregnancies with compromised fetal growth, while variations in transcriptional output from the expressed alleles of imprinted genes are more commonly reported in pregnancies complicated with intrauterine growth restriction (IUGR). To determine if PLAGL1 and HYMAI, two imprinted transcripts deregulated in Transient Neonatal Diabetes Mellitus, are involved in non-syndromic IUGR we compared the expression and DNA methylation levels in a large cohort of placental biopsies from IUGR and uneventful pregnancies. This revealed that despite appropriate maternal methylation at the shared PLAGL1/HYMAI promoter, there was a loss of correlation between PLAGL1 and HYMAI expression in IUGR. This incongruity was due to higher HYMAI expression in IUGR gestations, coupled with PLAGL1 down-regulation in placentas from IUGR girls, but not boys. The PLAGL1 protein is a zinc-finger transcription factor that has been shown to be a master coordinator of a genetic growth network in mice. We observe PLAGL1 binding to the H19/IGF2 shared enhancers in placentae, with significant correlations between PLAGL1 levels with H19 and IGF2 expression levels. In addition, PLAGL1 binding and expression also correlate with expression levels of metabolic regulator genes SLC2A4, TCF4 and PPARγ1. Our results strongly suggest that fetal growth can be influenced by altered expression of the PLAGL1 gene network in human placenta.

  6. Tyrosine Kinase Discoidin Domain Receptors DDR1 and DDR2 are Coordinately Deregulated in Triple Negative Breast Cancer

    PubMed Central

    Toy, Kathy A.; Valiathan, Rajeshwari R.; Núñez, Fernando; Kidwell, Kelley M.; Gonzalez, Maria E.; Fridman, Rafael; Kleer, Celina G.

    2016-01-01

    Purpose Receptor kinases Discoidin Domain Receptors (DDRs) 1 and 2 are emerging as new therapeutic targets in breast cancer (BC). However, the expression of DDR proteins during BC progression and their association with BC subtypes remain poorly defined. Herein we report the first comprehensive immunohistochemical analyses of DDR protein expression in a wide range of breast tissues. Methods DDR1 and DDR2 expression was investigated by immunohistochemistry in 218 samples of normal breast (n=10), ductal carcinoma in situ (DCIS, n=10), and invasive carcinomas (n=198), arrayed in tissue microarrays with comprehensive clinical and follow-up information. Staining was evaluated for cell type, subcellular localization, and percentage and intensity (scores 1–4) and association with disease subtype and outcome. Results In normal epithelium and DCIS, DDR1 was highly expressed, while DDR2 was negative in normal epithelium and in DCIS it localized to cells at the epithelial-stromal interface. Of the 198 invasive carcinomas, DDR1 was high in 87 (44%) and low in 103 (52%), and DDR2 was high in 110 (56%) and low in 87 (44%). High DDR2 was associated with high tumor grade (p=0.002), triple negative subtype (TNBC) (p<0.0001), and worse survival (p=0.037). We discovered a novel concordant deregulation of DDR expression, with a DDR1Low/DDR2High profile significantly associated with TNBC, compared to luminal tumors (p=0.012), and with worse overall survival. Conclusions DDR2 upregulation occurs in DCIS, before stromal invasion, and may reflect epithelial-stromal cross talk. A DDR1Low/DDR2High protein profile is associated with TNBC, and may identify invasive carcinomas with worse prognosis. PMID:25667101

  7. Lacrimal Gland Inflammation Deregulates Extracellular Matrix Remodeling and Alters Molecular Signature of Epithelial Stem/Progenitor Cells

    PubMed Central

    Umazume, Takeshi; Thomas, William M.; Campbell, Sabrina; Aluri, Hema; Thotakura, Suharika; Zoukhri, Driss; Makarenkova, Helen P.

    2015-01-01

    Purpose The adult lacrimal gland (LG) is highly regenerative and is able to repair itself even after substantial damage; however, this ability to regenerate is lost with the development of dry eye conditions in chronically inflamed LGs.This study compares changes in the cell adhesion and cell matrix molecules and stem cell transcription factors in the LGs of healthy mice and of two mouse models of Sjögren's syndrome: nonobese diabetic (NOD) and MRL-lpr/lpr (MRL/lpr) mice during the early stage of inflammation. Methods The LGs from 12- to 13-week-old female MRL/lpr and male NOD mice along with their respective control strains were harvested and divided into three pieces and processed for quantitative (q) RT-PCR and qRT-PCR Arrays, histology, immunohistochemistry, and Western blotting. Results The extracellular matrix (ECM) and adhesion molecules RT2-PCR array combined with protein expression data revealed changes in the expression of integrins, matrix metalloproteinases, and other molecules, which are associated largely with invasion, attachment, and expansion of the lymphocytic cells, whereas changes in the stem cell transcription factors revealed substantial decrease in expression of transcription factors associated with epithelial stem/progenitor cell lineage. Conclusions We concluded that the expression of several important ECM components is significantly deregulated in the LG of two murine models of Sjögren's syndrome, suggesting an alteration of the epithelial stem/progenitor cell niche. This may result in profound effects on localization, activation, proliferation, and differentiation of the LG stem/progenitor cells and, therefore, LG regeneration. PMID:26747770

  8. Tyrosine kinase discoidin domain receptors DDR1 and DDR2 are coordinately deregulated in triple-negative breast cancer.

    PubMed

    Toy, Kathy A; Valiathan, Rajeshwari R; Núñez, Fernando; Kidwell, Kelley M; Gonzalez, Maria E; Fridman, Rafael; Kleer, Celina G

    2015-02-01

    Receptor kinases Discoidin Domain Receptors (DDRs) 1 and 2 are emerging as new therapeutic targets in breast cancer (BC). However, the expression of DDR proteins during BC progression and their association with BC subtypes remain poorly defined. Herein we report the first comprehensive immunohistochemical analyses of DDR protein expression in a wide range of breast tissues. DDR1 and DDR2 expression was investigated by immunohistochemistry in 218 samples of normal breast (n = 10), ductal carcinoma in situ (DCIS, n = 10), and invasive carcinomas (n = 198), arrayed in tissue microarrays with comprehensive clinical and follow-up information. Staining was evaluated for cell type, subcellular localization, percentage and intensity (scores 1-4), and association with disease subtype and outcome. In normal epithelium and DCIS, DDR1 was highly expressed, while DDR2 was negative in normal epithelium, and in DCIS it localized to cells at the epithelial-stromal interface. Of the 198 invasive carcinomas, DDR1 was high in 87 (44 %) and low in 103 (52 %), and DDR2 was high in 110 (56 %) and low in 87 (44 %). High DDR2 was associated with high tumor grade (P = 0.002), triple-negative subtype (TNBC) (P < 0.0001), and worse survival (P = 0.037). We discovered a novel concordant deregulation of DDR expression, with a DDR1(Low)/DDR2(High) profile significantly associated with TNBC, compared to luminal tumors (P = 0.012), and with worse overall survival. In conclusion, DDR2 upregulation occurs in DCIS, before stromal invasion, and may reflect epithelial-stromal cross-talk. A DDR1(Low)/DDR2(High) protein profile is associated with TNBC and may identify invasive carcinomas with worse prognosis. PMID:25667101

  9. Altered expression of the imprinted transcription factor PLAGL1 deregulates a network of genes in the human IUGR placenta

    PubMed Central

    Iglesias-Platas, Isabel; Martin-Trujillo, Alex; Petazzi, Paolo; Guillaumet-Adkins, Amy; Esteller, Manel; Monk, David

    2014-01-01

    Genomic imprinting is the epigenetic process that results in monoallelic expression of genes depending on parental origin. These genes are known to be critical for placental development and fetal growth in mammals. Aberrant epigenetic profiles at imprinted loci, such as DNA methylation defects, are surprisingly rare in pregnancies with compromised fetal growth, while variations in transcriptional output from the expressed alleles of imprinted genes are more commonly reported in pregnancies complicated with intrauterine growth restriction (IUGR). To determine if PLAGL1 and HYMAI, two imprinted transcripts deregulated in Transient Neonatal Diabetes Mellitus, are involved in non-syndromic IUGR we compared the expression and DNA methylation levels in a large cohort of placental biopsies from IUGR and uneventful pregnancies. This revealed that despite appropriate maternal methylation at the shared PLAGL1/HYMAI promoter, there was a loss of correlation between PLAGL1 and HYMAI expression in IUGR. This incongruity was due to higher HYMAI expression in IUGR gestations, coupled with PLAGL1 down-regulation in placentas from IUGR girls, but not boys. The PLAGL1 protein is a zinc-finger transcription factor that has been shown to be a master coordinator of a genetic growth network in mice. We observe PLAGL1 binding to the H19/IGF2 shared enhancers in placentae, with significant correlations between PLAGL1 levels with H19 and IGF2 expression levels. In addition, PLAGL1 binding and expression also correlate with expression levels of metabolic regulator genes SLC2A4, TCF4 and PPARγ1. Our results strongly suggest that fetal growth can be influenced by altered expression of the PLAGL1 gene network in human placenta. PMID:24993786

  10. Calpain-mediated integrin deregulation as a novel mode of action for the anticancer gallium compound KP46.

    PubMed

    Jungwirth, Ute; Gojo, Johannes; Tuder, Theresa; Walko, Gernot; Holcmann, Martin; Schöfl, Thomas; Nowikovsky, Karin; Wilfinger, Nastasia; Schoonhoven, Sushilla; Kowol, Christian R; Lemmens-Gruber, Rosa; Heffeter, Petra; Keppler, Bernhard K; Berger, Walter

    2014-10-01

    On the basis of enhanced tumor accumulation and bone affinity, gallium compounds are under development as anticancer and antimetastatic agents. In this study, we analyzed molecular targets of one of the lead anticancer gallium complexes [KP46, Tris(8-quinolinolato)gallium(III)] focusing on colon and lung cancer. Within a few hours, KP46 treatment at low micromolar concentrations induced cell body contraction and loss of adhesion followed by prompt cell decomposition. This rapid KP46-induced cell death lacked classic apoptotic features and was insensitive toward a pan-caspase inhibitor. Surprisingly, however, it was accompanied by upregulation of proapoptotic Bcl-2 family members. Furthermore, a Bax- but not a p53-knockout HCT-116 subline exhibited significant KP46 resistance. Rapid KP46-induced detachment was accompanied by downregulation of focal adhesion proteins, including several integrin subunits. Loss of integrin-β1 and talin plasma membrane localization corresponded to reduced binding of RGD (Arg-Gly-Asp) peptides to KP46-treated cells. Accordingly, KP46-induced cell death and destabilization of integrins were enhanced by culture on collagen type I, a major integrin ligand. In contrast, KP46-mediated adhesion defects were partially rescued by Mg(2+) ions, promoting integrin-mediated cell adhesion. Focal adhesion dynamics are regulated by calpains via cleavage of multiple cell adhesion molecules. Cotreatment with the cell-permeable calpain inhibitor PD150606 diminished KP46-mediated integrin destabilization and rapid cell death induction. KP46 treatment distinctly inhibited HCT-116 colon cancer xenograft in vivo by causing reduced integrin plasma membrane localization, tissue disintegration, and intense tumor necrosis. This study identifies integrin deregulation via a calpain-mediated mechanism as a novel mode of action for the anticancer gallium compound KP46.

  11. Deregulation of Annexin-A1 and Galectin-1 Expression in Precancerous Gastric Lesions: Intestinal Metaplasia and Gastric Ulcer

    PubMed Central

    Rossi, Ana Flávia Teixeira; Duarte, Márcia Cristina; Poltronieri, Ayla Blanco; Valsechi, Marina Curado; Jorge, Yvana Cristina; de-Santi Neto, Dalísio; Rahal, Paula; Oliani, Sonia Maria; Silva, Ana Elizabete

    2014-01-01

    Objective. Annexin-A1 (ANXA1/AnxA1) and galectin-1 (LGALS1/Gal-1) are mediators that play an important role in the inflammatory response and are also associated with carcinogenesis. We investigated mRNA and protein expression in precancerous gastric lesions that participate in the progression cascade to gastric cancer, such as intestinal metaplasia (IM) and gastric ulcer (GU). Methods. Quantitative real-time PCR (qPCR) and immunohistochemical techniques were used to analyze the relative quantification levels (RQ) of ANXA1 and LGALS1 mRNA and protein expression, respectively. Results. Increased relative expression levels of ANXA1 were found in 100% of cases, both in IM (mean RQ = 6.22 ± 0.06) and in GU (mean RQ = 6.69 ± 0.10). However, the LGALS1 presented basal expression in both groups (IM: mean RQ = 0.35 ± 0.07; GU: mean RQ = 0.69 ± 0.09). Immunohistochemistry revealed significant positive staining for both the AnxA1 and Gal-1 proteins in the epithelial nucleus and cytoplasm as well as in the stroma of the IM and GU groups (P < 0.05) but absence or low immunorectivity in normal mucosa. Conclusion. Our results bring an important contribution by evidencing that both the AnxA1 and Gal-1 anti-inflammatory proteins are deregulated in precancerous gastric lesions, suggesting their involvement in the early stages of gastric carcinogenesis, possibly due to an inflammatory process in the gastric mucosa. PMID:24719523

  12. Deregulated expression of annexin-A2 and galectin-3 is associated with metastasis in gastric cancer patients.

    PubMed

    Leal, Mariana Ferreira; Calcagno, Danielle Queiroz; Chung, Janete; de Freitas, Vanessa Morais; Demachki, Samia; Assumpção, Paulo Pimentel; Chammas, Roger; Burbano, Rommel Rodríguez; Smith, Marília Cardoso

    2015-08-01

    Gastric cancer (GC) is the second highest cause of cancer mortality worldwide. However, nowadays, most of the studies aiming to understand the gastric carcinogenesis analyzed tumors of individuals from Asian population and, thus, may not reflect the distinct biological and clinical behaviors among GC processes. Since several membrane proteins have been implicated in carcinogenesis, we aimed to evaluate ANXA2 and GAL3 role in gastric tumors and GC cell lines of individuals from northern Brazil. The cellular localization of ANXA2 and GAL3 in the GC cell lines was evaluated by immunofluorescence. Gene expression was evaluated by real-time reverse-transcription PCR and protein expression by Western blot in gastric adenocarcinomas and non-neoplastic gastric samples, as well as in GC cell lines. ANXA2 and GAL3 were presented as dots in the plasma membrane and cytoplasm in ACP02 and ACP03 cell lines. ANXA2 mRNA expression was up-regulated in 32.14 % of gastric tumors compared to non-neoplastic tissues. ANXA2 up-regulation was associated with the metastasis process in vivo and with cell line invasive behavior. GAL3 protein expression was at least 1.5-fold reduced in 50 % of gastric tumors. The reduced GAL3 expression was associated with the presence of distant metastasis and with a higher invasive phenotype in vitro. Our study shows that ANXA2 and GAL3 deregulated expression was associated with an invasive phenotype in GC cell lines and may contribute to metastasis in GC patients. Therefore, these proteins may have potential prognostic relevance for GC of individuals from northern Brazil. PMID:25034653

  13. The monocytic population in chronic lymphocytic leukemia shows altered composition and deregulation of genes involved in phagocytosis and inflammation

    PubMed Central

    Maffei, Rossana; Bulgarelli, Jenny; Fiorcari, Stefania; Bertoncelli, Linda; Martinelli, Silvia; Guarnotta, Carla; Castelli, Ilaria; Deaglio, Silvia; Debbia, Giulia; De Biasi, Sara; Bonacorsi, Goretta; Zucchini, Patrizia; Narni, Franco; Tripodo, Claudio; Luppi, Mario; Cossarizza, Andrea; Marasca, Roberto

    2013-01-01

    Macrophages reside in tissues infiltrated by chronic lymphocytic leukemia B cells and the extent of infiltration is associated with adverse prognostic factors. We studied blood monocyte population by flow cytometry and whole-genome microarrays. A mixed lymphocyte reaction was performed to evaluate proliferation of T cells in contact with monocytes from patients and normal donors. Migration and gene modulation in normal monocytes cultured with CLL cells were also evaluated. The absolute number of monocytes increased in chronic lymphocytic leukemia patients compared to the number in normal controls (792±86 cells/μL versus 485±46 cells/μL, P=0.003). Higher numbers of non-classical CD14+CD16++ and Tie-2-expressing monocytes were also detected in patients. Furthermore, we performed a gene expression analysis of monocytes in chronic lymphocytic leukemia patients, showing up-regulation of RAP1GAP and down-regulation of tubulins and CDC42EP3, which would be expected to result in impairment of phagocytosis. We also detected gene alterations such as down-regulation of PTGR2, a reductase able to inactivate prostaglandin E2, indicating immunosuppressive activity. Accordingly, the proliferation of T cells in contact with monocytes from patients was inhibited compared to that of cells in contact with monocytes from normal controls. Finally, normal monocytes in vitro increased migration and up-regulated CD16, RAP1GAP, IL-10, IL-8, MMP9 and down-regulated PTGR2 in response to leukemic cells or conditioned media. In conclusion, altered composition and deregulation of genes involved in phagocytosis and inflammation were found in blood monocytes obtained from chronic lymphocytic leukemia patients, suggesting that leukemia-mediated “education” of immune elements may also include the establishment of a skewed phenotype in the monocyte/macrophage population. PMID:23349302

  14. Nash equilibrium strategy in the deregulated power industry and comparing its lost welfare with Iran wholesale electricity market

    NASA Astrophysics Data System (ADS)

    Mousavi, Seyed Hosein; Nazemi, Ali; Hafezalkotob, Ashkan

    2016-07-01

    With the increasing use of different types of auctions in market designing, modeling of participants' behaviors to evaluate the market structure is one of the main discussions in the studies related to the deregulated power industries. In this article, we apply an approach of the optimal bidding behavior to the Iran wholesale electricity market as a restructured electric power industry and model how the participants of the market bid in the spot electricity market. The problem is formulated analytically using the Nash equilibrium concept composed of large numbers of players having discrete and very large strategy spaces. Then, we compute and draw supply curve of the competitive market in which all generators' proposed prices are equal to their marginal costs and supply curve of the real market in which the pricing mechanism is pay-as-bid. We finally calculate the lost welfare or inefficiency of the Nash equilibrium and the real market by comparing their supply curves with the competitive curve. We examine 3 cases on November 24 (2 cases) and July 24 (1 case), 2012. It is observed that in the Nash equilibrium on November 24 and demand of 23,487 MW, there are 212 allowed plants for the first case (plants are allowed to choose any quantity of generation except one of them that should be equal to maximum Power) and the economic efficiency or social welfare of Nash equilibrium is 2.77 times as much as the real market. In addition, there are 184 allowed plants for the second case (plants should offer their maximum power with different prices) and the efficiency or social welfare of Nash equilibrium is 3.6 times as much as the real market. On July 24 and demand of 42,421 MW, all 370 plants should generate maximum energy due to the high electricity demand that the economic efficiency or social welfare of the Nash equilibrium is about 2 times as much as the real market.

  15. IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation

    PubMed Central

    Oktay, Yavuz; Ülgen, Ege; Can, Özge; Akyerli, Cemaliye B.; Yüksel, Şirin; Erdemgil, Yiğit; Durası, İ. Melis; Henegariu, Octavian Ioan; Nanni, E. Paolo; Selevsek, Nathalie; Grossmann, Jonas; Erson-Omay, E. Zeynep; Bai, Hanwen; Gupta, Manu; Lee, William; Turcan, Şevin; Özpınar, Aysel; Huse, Jason T.; Sav, M. Aydın; Flanagan, Adrienne; Günel, Murat; Sezerman, O. Uğur; Yakıcıer, M. Cengiz; Pamir, M. Necmettin; Özduman, Koray

    2016-01-01

    The single nucleotide polymorphism rs55705857, located in a non-coding but evolutionarily conserved region at 8q24.21, is strongly associated with IDH-mutant glioma development and was suggested to be a causal variant. However, the molecular mechanism underlying this association has remained unknown. With a case control study in 285 gliomas, 316 healthy controls, 380 systemic cancers, 31 other CNS-tumors, and 120 IDH-mutant cartilaginous tumors, we identified that the association was specific to IDH-mutant gliomas. Odds-ratios were 9.25 (5.17–16.52; 95% CI) for IDH-mutated gliomas and 12.85 (5.94–27.83; 95% CI) for IDH-mutated, 1p/19q co-deleted gliomas. Decreasing strength with increasing anaplasia implied a modulatory effect. No somatic mutations were noted at this locus in 114 blood-tumor pairs, nor was there a copy number difference between risk-allele and only-ancestral allele carriers. CCDC26 RNA-expression was rare and not different between the two groups. There were only minor subtype-specific differences in common glioma driver genes. RNA sequencing and LC-MS/MS comparisons pointed to significantly altered MYC-signaling. Baseline enhancer activity of the conserved region specifically on the MYC promoter and its further positive modulation by the SNP risk-allele was shown in vitro. Our findings implicate MYC deregulation as the underlying cause of the observed association. PMID:27282637

  16. Effect of neurotrophin-3 precursor on glutamate-induced calcium homeostasis deregulation in rat cerebellum granule cells.

    PubMed

    Safina, Dina R; Surin, Alexander M; Pinelis, Vsevolod G; Kostrov, Sergey V

    2015-12-01

    Neurotrophin-3 (NT-3) belongs to the family of highly conserved dimeric growth factors that controls the differentiation and activity of various neuronal populations. Mammals contain both the mature (NT-3) and the precursor (pro-NT-3) forms of neurotrophin. Members of the neurotrophin family are involved in the regulation of calcium homeostasis in neurons; however, the role of NT-3 and pro-NT-3 in this process remains unclear. The current study explores the effects of NT-3 and pro-NT-3 on disturbed calcium homeostasis and decline of mitochondrial potential induced by a neurotoxic concentration of glutamate (Glu; 100 µM) in the primary culture of rat cerebellar granule cells. In this Glu excitotoxicity model, mature NT-3 had no effect on the induced changes in Ca²⁺ homeostasis. In contrast, pro-NT-3 decreased the period of delayed calcium deregulation (DCD) and concurrent strong mitochondrial depolarization. According to the amplitude of the increase in the intracellular free Ca²⁺ concentration ([Ca²⁺]i ) and Fura-2 fluorescence quenching by Mn²⁺ within the first 20 sec of exposure to Glu, pro-NT-3 had no effect on the initial rate of Ca²⁺ entry into neurons. During the lag period preceding DCD, the mean amplitude of [Ca²⁺]i rise was 1.2-fold greater in the presence of pro-NT-3 than in the presence of Glu alone (1.67 ±  0.07 and 1.39 ± 0.04, respectively, P < 0.05). The Glu-induced changes in Са²⁺ homeostasis in the presence of pro-NT-3 likely are due to the decreased rate of Са²⁺ removal from the cytosol during the DCD latency period.

  17. Sustainability in Brazilian Federal Universities

    ERIC Educational Resources Information Center

    Palma, Lisiane Celia; de Oliveira, Lessandra M.; Viacava, Keitiline R.

    2011-01-01

    Purpose: The purpose of this paper is to identify the number of courses related to sustainability offered in bachelor degree programs of business administration in Brazilian federal universities. Design/methodology/approach: An exploratory research was carried out based on a descriptive scope. The process of mapping federal universities in Brazil…

  18. Deceptive Business Practices: Federal Regulations.

    ERIC Educational Resources Information Center

    Rohrer, Daniel Morgan

    Federal regulations to prevent deceptive advertising seek to balance the advertiser's freedom of speech with protection of the consumer. This paper discusses what the Federal Trade Commission (FTC) has done to regulate advertising and evaluates the adequacy of its controls. The commission uses cease-and-desist orders, affirmative disclosure,…

  19. Priorities for Federal Education Statistics.

    ERIC Educational Resources Information Center

    Murnane, Richard J.

    The paper suggests priorities for the federal government's elementary and secondary education data collection efforts. Sections on outputs, inputs, and private schools describe what data is needed, what is already available, and what is recommended for data collection. Recommendations include a high priority for federal funding for the National…

  20. Federal Policy and Graduate Education.

    ERIC Educational Resources Information Center

    Snyder, Robert

    What role should the federal government play in support of graduate education? Based on the principles that: (1) American graduate education and research establishment is a national resource; (2) the market for highly trained manpower is national; (3) the federal government itself employs the service of many highly trained personnel; (4) it is in…

  1. Epigenetic deregulations in chordoma.

    PubMed

    Yu, Xin; Li, Zheng

    2015-10-01

    Chordoma is a rare type of malignant bone tumour arising from remnant notochord and prognosis of patients with it remains poor as its molecular and genetic mechanisms are not well understood. Increasing evidence has demonstrated that epigenetic mechanisms (DNA methylation, histone modification and nucleosome remodelling), play a crucial role in the pathogenesis of many diseases. Aberrant epigenetic patterns are present in patients with chordoma, indicating a potential role for epigenetic mechanisms inthis malignancy. Furthermore, epigenetic alterations may provide novel biomarkers for diagnosis and prognosis as well as therapeutic targets for treatment. In this review, we discuss relevant epigenetic findings associated with chordoma, and their potential application for diagnosis, prognosis and treatment.

  2. Changes in cortical cytoskeletal and extracellular matrix gene expression in prostate cancer are related to oncogenic ERG deregulation

    PubMed Central

    2010-01-01

    appear to be associated with oncogenic ERG overexpression. We hypothesize that these alterations may contribute to the increased invasivity conferred to prostate cancer cells by ERG deregulation. PMID:20860828

  3. Intrinsic Deregulation of Vascular Smooth Muscle and Myofibroblast Differentiation in Mesenchymal Stromal Cells from Patients with Systemic Sclerosis

    PubMed Central

    Hegner, Björn; Schaub, Theres; Catar, Rusan; Kusch, Angelika; Wagner, Philine; Essin, Kirill; Lange, Claudia; Riemekasten, Gabriela; Dragun, Duska

    2016-01-01

    Introduction Obliterative vasculopathy and fibrosis are hallmarks of systemic sclerosis (SSc), a severe systemic autoimmune disease. Bone marrow-derived mesenchymal stromal cells (MSCs) from SSc patients may harbor disease-specific abnormalities. We hypothesized disturbed vascular smooth muscle cell (VSMC) differentiation with increased propensity towards myofibroblast differentiation in response to SSc-microenvironment defining growth factors and determined responsible mechanisms. Methods We studied responses of multipotent MSCs from SSc-patients (SSc-MSCs) and healthy controls (H-MSCs) to long-term exposure to CTGF, b-FGF, PDGF-BB or TGF-β1. Differentiation towards VSMC and myofibroblast lineages was analyzed on phenotypic, biochemical, and functional levels. Intracellular signaling studies included analysis of TGF-β receptor regulation, SMAD, AKT, ERK1/2 and autocrine loops. Results VSMC differentiation towards both, contractile and synthetic VSMC phenotypes in response to CTGF and b-FGF was disturbed in SSc-MSCs. H-MSCs and SSc-MSCs responded equally to PDGF-BB with prototypic fibroblastic differentiation. TGF-β1 initiated myofibroblast differentiation in both cell types, yet with striking phenotypic and functional differences: In relation to H-MSC-derived myofibroblasts induced by TGF-β1, those obtained from SSc-MSCs expressed more contractile proteins, migrated towards TGF-β1, had low proliferative capacity, and secreted higher amounts of collagen paralleled by reduced MMP expression. Higher levels of TGF-β receptor 1 and enhanced canonical and noncanonical TGF-β signaling in SSc-MSCs accompanied aberrant differentiation response of SSc-MSCs in comparison to H-MSCs. Conclusions Deregulated VSMC differentiation with a shift towards myofibroblast differentiation expands the concept of disturbed endogenous regenerative capacity of MSCs from SSc patients. Disease related intrinsic hyperresponsiveness to TGF-β1 with increased collagen production may

  4. ‘N-of-1-pathways’ unveils personal deregulated mechanisms from a single pair of RNA-Seq samples: towards precision medicine

    PubMed Central

    Gardeux, Vincent; Achour, Ikbel; Li, Jianrong; Maienschein-Cline, Mark; Li, Haiquan; Pesce, Lorenzo; Parinandi, Gurunadh; Bahroos, Neil; Winn, Robert; Foster, Ian; Garcia, Joe G N; Lussier, Yves A

    2014-01-01

    Background The emergence of precision medicine allowed the incorporation of individual molecular data into patient care. Indeed, DNA sequencing predicts somatic mutations in individual patients. However, these genetic features overlook dynamic epigenetic and phenotypic response to therapy. Meanwhile, accurate personal transcriptome interpretation remains an unmet challenge. Further, N-of-1 (single-subject) efficacy trials are increasingly pursued, but are underpowered for molecular marker discovery. Method ‘N-of-1-pathways’ is a global framework relying on three principles: (i) the statistical universe is a single patient; (ii) significance is derived from geneset/biomodules powered by paired samples from the same patient; and (iii) similarity between genesets/biomodules assesses commonality and differences, within-study and cross-studies. Thus, patient gene-level profiles are transformed into deregulated pathways. From RNA-Seq of 55 lung adenocarcinoma patients, N-of-1-pathways predicts the deregulated pathways of each patient. Results Cross-patient N-of-1-pathways obtains comparable results with conventional genesets enrichment analysis (GSEA) and differentially expressed gene (DEG) enrichment, validated in three external evaluations. Moreover, heatmap and star plots highlight both individual and shared mechanisms ranging from molecular to organ-systems levels (eg, DNA repair, signaling, immune response). Patients were ranked based on the similarity of their deregulated mechanisms to those of an independent gold standard, generating unsupervised clusters of diametric extreme survival phenotypes (p=0.03). Conclusions The N-of-1-pathways framework provides a robust statistical and relevant biological interpretation of individual disease-free survival that is often overlooked in conventional cross-patient studies. It enables mechanism-level classifiers with smaller cohorts as well as N-of-1 studies. Software http://lussierlab.org/publications/N-of-1-pathways

  5. Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water

    SciTech Connect

    Muñoz, Alexandra; Chervona, Yana; Hall, Megan; Kluz, Thomas; Gamble, Mary V.; Costa, Max

    2015-05-01

    Arsenic contamination of drinking water occurs globally and is associated with numerous diseases including skin, lung and bladder cancers, and cardiovascular disease. Recent research indicates that arsenic may be an endocrine disruptor. This study was conducted to evaluate the nature of gene expression changes among males and females exposed to arsenic contaminated water in Bangladesh at high and low doses. Twenty-nine (55% male) Bangladeshi adults with water arsenic exposure ranging from 50 to 1000 μg/L were selected from the Folic Acid Creatinine Trial. RNA was extracted from peripheral blood mononuclear cells for gene expression profiling using Affymetrix 1.0 ST arrays. Differentially expressed genes were assessed between high and low exposure groups for males and females separately and findings were validated using quantitative real-time PCR. There were 534 and 645 differentially expressed genes (p < 0.05) in the peripheral blood mononuclear cells of males and females, respectively, when high and low water arsenic exposure groups were compared. Only 43 genes overlapped between the two sexes, with 29 changing in opposite directions. Despite the difference in gene sets both males and females exhibited common biological changes including deregulation of 17β-hydroxysteroid dehydrogenase enzymes, deregulation of genes downstream of Sp1 (specificity protein 1) transcription factor, and prediction of estrogen receptor alpha as a key hub in cardiovascular networks. Arsenic-exposed adults exhibit sex-specific gene expression profiles that implicate involvement of the endocrine system. Due to arsenic's possible role as an endocrine disruptor, exposure thresholds for arsenic may require different parameters for males and females. - Highlights: • Males and females exhibit unique gene expression changes in response to arsenic. • Only 23 genes are common among the differentially expressed genes for the sexes. • Male and female gene lists exhibit common biological

  6. ‘N-of-1- pathways ’ unveils personal deregulated mechanisms from a single pair of RNA-Seq samples: Towards precision medicine

    SciTech Connect

    Gardeux, Vincent; Achour, Ikbel; Li, Jianrong; Maienschein-Cline, Mark; Li, Haiquan; Pesce, Lorenzo; Parinandi, Gurunadh; Bahroos, Neil; Winn, Robert; Garcia, Joe G. N.; Foster, Ian; Lussier, Yves A.

    2014-11-01

    Background: The emergence of precision medicine allowed the incorporation of individual molecular data into patient care. This research entails, DNA sequencing predicts somatic mutations in individual patients. However, these genetic features overlook dynamic epigenetic and phenotypic response to therapy. Meanwhile, accurate personal transcriptome interpretation remains an unmet challenge. Further, N-of-1 (single-subject) efficacy trials are increasingly pursued, but are underpowered for molecular marker discovery. Method: ‘N-of-1-pathways’ is a global framework relying on three principles: (i) the statistical universe is a single patient; (ii) significance is derived from geneset/biomodules powered by paired samples from the same patient; and (iii) similarity between genesets/biomodules assesses commonality and differences, within-study and cross-studies. Thus, patient gene-level profiles are transformed into deregulated pathways. From RNA-Seq of 55 lung adenocarcinoma patients, N-of-1-pathways predicts the deregulated pathways of each patient. Results: Cross-patient N-of-1-pathways obtains comparable results with conventional genesets enrichment analysis (GSEA) and differentially expressed gene (DEG) enrichment, validated in three external evaluations. Moreover, heatmap and star plots highlight both individual and shared mechanisms ranging from molecular to organ-systems levels (eg, DNA repair, signaling, immune response). Patients were ranked based on the similarity of their deregulated mechanisms to those of an independent gold standard, generating unsupervised clusters of diametric extreme survival phenotypes (p=0.03). Conclusions: The N-of-1-pathways framework provides a robust statistical and relevant biological interpretation of individual disease-free survival that is often overlooked in conventional cross-patient studies. It enables mechanism-level classifiers with smaller cohorts as well as N-of-1 studies.

  7. ‘N-of-1- pathways ’ unveils personal deregulated mechanisms from a single pair of RNA-Seq samples: Towards precision medicine

    DOE PAGES

    Gardeux, Vincent; Achour, Ikbel; Li, Jianrong; Maienschein-Cline, Mark; Li, Haiquan; Pesce, Lorenzo; Parinandi, Gurunadh; Bahroos, Neil; Winn, Robert; Garcia, Joe G. N.; et al

    2014-11-01

    Background: The emergence of precision medicine allowed the incorporation of individual molecular data into patient care. This research entails, DNA sequencing predicts somatic mutations in individual patients. However, these genetic features overlook dynamic epigenetic and phenotypic response to therapy. Meanwhile, accurate personal transcriptome interpretation remains an unmet challenge. Further, N-of-1 (single-subject) efficacy trials are increasingly pursued, but are underpowered for molecular marker discovery. Method: ‘N-of-1-pathways’ is a global framework relying on three principles: (i) the statistical universe is a single patient; (ii) significance is derived from geneset/biomodules powered by paired samples from the same patient; and (iii) similarity between genesets/biomodulesmore » assesses commonality and differences, within-study and cross-studies. Thus, patient gene-level profiles are transformed into deregulated pathways. From RNA-Seq of 55 lung adenocarcinoma patients, N-of-1-pathways predicts the deregulated pathways of each patient. Results: Cross-patient N-of-1-pathways obtains comparable results with conventional genesets enrichment analysis (GSEA) and differentially expressed gene (DEG) enrichment, validated in three external evaluations. Moreover, heatmap and star plots highlight both individual and shared mechanisms ranging from molecular to organ-systems levels (eg, DNA repair, signaling, immune response). Patients were ranked based on the similarity of their deregulated mechanisms to those of an independent gold standard, generating unsupervised clusters of diametric extreme survival phenotypes (p=0.03). Conclusions: The N-of-1-pathways framework provides a robust statistical and relevant biological interpretation of individual disease-free survival that is often overlooked in conventional cross-patient studies. It enables mechanism-level classifiers with smaller cohorts as well as N-of-1 studies.« less

  8. 41 CFR 102-79.40 - Can Federal agencies allot space in Federal buildings to Federal credit unions?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false Can Federal agencies allot space in Federal buildings to Federal credit unions? 102-79.40 Section 102-79.40 Public Contracts and Property Management Federal Property Management Regulations System (Continued) FEDERAL MANAGEMENT REGULATION REAL PROPERTY 79-ASSIGNMENT...

  9. 77 FR 31600 - Federal Need Analysis Methodology for the 2013-2014 Award Year: Federal Pell Grant, Federal...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-29

    ..., Federal Work-Study, Federal Supplemental Educational Opportunity Grant, William D. Ford Federal Direct... Supplemental Educational Opportunity Grant Program; 84.268 William D. Ford Federal Direct Loan Program; 84.379.... Ford Federal Direct Loan, and the Teach Grant Programs (title IV, HEA programs). FOR...

  10. Federal Employees Responsible Investment Act

    THOMAS, 112th Congress

    Rep. Langevin, James R. [D-RI-2

    2011-06-03

    06/20/2011 Referred to the Subcommittee on Federal Workforce, U.S. Postal Service, and Labor Policy . (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

  11. Federal Life Insurance Transparency Act

    THOMAS, 112th Congress

    Rep. Connolly, Gerald E. [D-VA-11

    2011-01-05

    02/08/2011 Referred to the Subcommittee on Federal Workforce, U.S. Postal Service, and Labor Policy . (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

  12. Federal Firefighter Pay Equity Act

    THOMAS, 111th Congress

    Rep. Connolly, Gerald E. [D-VA-11

    2009-07-13

    07/31/2009 Referred to the Subcommittee on Federal Workforce, Post Office, and the District of Columbia. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

  13. Federal Firefighter Pay Equity Act

    THOMAS, 112th Congress

    Rep. Connolly, Gerald E. [D-VA-11

    2011-03-14

    04/01/2011 Referred to the Subcommittee on Federal Workforce, U.S. Postal Service, and Labor Policy. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

  14. Federal Renewable Energy Screening Assistant

    SciTech Connect

    Shelpuk, B; Walker, A

    1994-10-01

    The Federal Renewable Energy Screening Assistant is a software tool to be used by energy auditors to prioritize future studies of potentially cost-effective renewable energy applications at federal facilities. This paper describes the structure and function of the tool, gives an inventory of renewable energy technologies represented in the tool, and briefly describes the algorithms used to rank opportunities by the savings-to-investment ratio.

  15. Federal technology policy in transition

    SciTech Connect

    Carnes, K.H.

    1995-12-31

    This paper discusses federal energy and environmental policies and their impact on the U.S. economy. A brief history of the federal government`s role in developing scientific and technological infrastructure is given. Current trends in technology are summarized, with an emphasis on global aspects, and their impact on the economy is discussed. The need for a national technology policy, including continued research and development funding, is discussed and key elements of such a policy are outlined.

  16. Mitigating earthquakes; the federal role

    USGS Publications Warehouse

    Press, F.

    1977-01-01

    With rapid approach of a capability to make reliable earthquake forecasts, it essential that the Federal Government play a strong, positive role in formulating and implementing plans to reduce earthquake hazards. Many steps are being taken in this direction, with the President looking to the Office of Science and Technology Policy (OSTP) in his Executive Office to provide leadership in establishing and coordinating Federal activities. 

  17. 23 CFR 646.212 - Federal share.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 23 Highways 1 2011-04-01 2011-04-01 false Federal share. 646.212 Section 646.212 Highways FEDERAL...-Highway Projects § 646.212 Federal share. (a) General. (1) Federal funds are not eligible to participate... required by a State regulatory agency. (b) The Federal share of railroad/highway crossing projects may...

  18. 23 CFR 646.212 - Federal share.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 23 Highways 1 2012-04-01 2012-04-01 false Federal share. 646.212 Section 646.212 Highways FEDERAL...-Highway Projects § 646.212 Federal share. (a) General. (1) Federal funds are not eligible to participate... required by a State regulatory agency. (b) The Federal share of railroad/highway crossing projects may...

  19. 23 CFR 646.212 - Federal share.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 23 Highways 1 2014-04-01 2014-04-01 false Federal share. 646.212 Section 646.212 Highways FEDERAL...-Highway Projects § 646.212 Federal share. (a) General. (1) Federal funds are not eligible to participate... required by a State regulatory agency. (b) The Federal share of railroad/highway crossing projects may...

  20. 23 CFR 646.212 - Federal share.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 23 Highways 1 2013-04-01 2013-04-01 false Federal share. 646.212 Section 646.212 Highways FEDERAL...-Highway Projects § 646.212 Federal share. (a) General. (1) Federal funds are not eligible to participate... required by a State regulatory agency. (b) The Federal share of railroad/highway crossing projects may...

  1. 23 CFR 646.212 - Federal share.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 23 Highways 1 2010-04-01 2010-04-01 false Federal share. 646.212 Section 646.212 Highways FEDERAL...-Highway Projects § 646.212 Federal share. (a) General. (1) Federal funds are not eligible to participate... required by a State regulatory agency. (b) The Federal share of railroad/highway crossing projects may...

  2. Federal Trade Commission Semiannual Regulatory Agenda

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-26

    ... Part XX Federal Trade Commission Semiannual Regulatory Agenda ] FEDERAL TRADE COMMISSION (FTC) FEDERAL TRADE COMMISSION 16 CFR Ch. I Semiannual Regulatory Agenda AGENCY: Federal Trade Commission... published in accordance with section 22(d)(1) of the Federal Trade Commission Act, 15 U.S.C.......

  3. 1 CFR 12.1 - Federal Register.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... PUBLICATIONS OFFICIAL DISTRIBUTION WITHIN FEDERAL GOVERNMENT § 12.1 Federal Register. (a) Copies of the daily... Federal Register Index and LSA (List of CFR Sections Affected) are included with each Federal Register... 1 General Provisions 1 2014-01-01 2012-01-01 true Federal Register. 12.1 Section 12.1...

  4. 1 CFR 12.1 - Federal Register.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... PUBLICATIONS OFFICIAL DISTRIBUTION WITHIN FEDERAL GOVERNMENT § 12.1 Federal Register. (a) Copies of the daily... Federal Register Index and LSA (List of CFR Sections Affected) are included with each Federal Register... 1 General Provisions 1 2013-01-01 2012-01-01 true Federal Register. 12.1 Section 12.1...

  5. 1 CFR 12.1 - Federal Register.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... PUBLICATIONS OFFICIAL DISTRIBUTION WITHIN FEDERAL GOVERNMENT § 12.1 Federal Register. (a) Copies of the daily... Federal Register Index and LSA (List of CFR Sections Affected) are included with each Federal Register... 1 General Provisions 1 2012-01-01 2012-01-01 false Federal Register. 12.1 Section 12.1...

  6. 1 CFR 12.1 - Federal Register.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Federal Register Index and LSA (List of CFR Sections Affected) are included with each Federal Register... 1 General Provisions 1 2010-01-01 2010-01-01 false Federal Register. 12.1 Section 12.1 General... PUBLICATIONS OFFICIAL DISTRIBUTION WITHIN FEDERAL GOVERNMENT § 12.1 Federal Register. (a) Copies of the...

  7. 1 CFR 12.1 - Federal Register.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Federal Register Index and LSA (List of CFR Sections Affected) are included with each Federal Register... 1 General Provisions 1 2011-01-01 2011-01-01 false Federal Register. 12.1 Section 12.1 General... PUBLICATIONS OFFICIAL DISTRIBUTION WITHIN FEDERAL GOVERNMENT § 12.1 Federal Register. (a) Copies of the...

  8. Differential antioxidant defense and detoxification mechanisms in photodynamically stressed rice plants treated with the deregulators of porphyrin biosynthesis, 5-aminolevulinic acid and oxyfluorfen.

    PubMed

    Phung, Thu-Ha; Jung, Sunyo

    2015-04-01

    This study focuses on differential molecular mechanisms of antioxidant and detoxification systems in rice plants under two different types of photodynamic stress imposed by porphyrin deregulators, 5-aminolevulinic acid (ALA) and oxyfluorfen (OF). The ALA-treated plants with white necrosis exhibited a greater decrease in photochemical quantum efficiency, Fv/Fm, as well as a greater increase in activity of superoxide dismutase, compared to the OF-treated plants. By contrast, the brown necrosis in OF-treated plants resulted in not only more widely dispersed H2O2 production and greater increases in H2O2-decomposing enzymes, catalase and peroxidase, but also lower ascorbate redox state. In addition, ALA- and OF-treated plants markedly up-regulated transcript levels of genes involved in detoxification processes including transport and movement, cellular homeostasis, and xenobiotic conjugation, with prominent up-regulation of serine/threonine kinase and chaperone only in ALA-treated plants. Our results demonstrate that different photodynamic stress imposed by ALA and OF developed differential actions of antioxidant enzymes and detoxification. Particularly, detoxification system may play potential roles in plant protection against photodynamic stress imposed by porphyrin deregulators, thereby contributing to alleviation of photodynamic damage.

  9. MiR-424 and miR-155 deregulated expression in cytogenetically normal acute myeloid leukaemia: correlation with NPM1 and FLT3 mutation status

    PubMed Central

    2012-01-01

    Background MicroRNA have a central role in normal haematopoiesis and are deregulated in acute myeloid leukaemia (AML). The purpose of the study was to investigate by qRT-PCR the expression of miRNAs involved in myeloid differentiation (miR-424, miR-155, miR-223, miR-17-5p) in 48 patients with cytogenetically normal AML well characterized for NPM1 and/or FLT3 mutations. Three types of normalization were used for the data validation. Findings We found that miR-424 was down-modulated in AMLs with NPM1mutA regardless of FLT3 status. On the contrary, miR-155 showed up-regulation in patients with FLT3 internal tandem duplications (ITD) with or without NPM1 mutations. No significant associations were found by analyzing miR-223 and miR-17-5p in relation to FLT3 and NPM1 status. Conclusions This study supports the view that major genetic subsets of CN-AML are associated with distinct miRNA signatures and suggests that miR-424 and miR-155 deregulation is involved in the pathogenesis of CN-AML with NPM1 and FLT3-ITD mutations, respectively. PMID:22681934

  10. Deregulation of Rb-E2F1 Axis Causes Chromosomal Instability by Engaging the Transactivation Function of Cdc20–Anaphase-Promoting Complex/Cyclosome

    PubMed Central

    Nath, Somsubhra; Chowdhury, Abhishek; Dey, Sanjib; Roychoudhury, Anirban; Ganguly, Abira; Bhattacharyya, Dibyendu

    2014-01-01

    The E2F family of transcription factors regulates genes involved in various aspects of the cell cycle. Beyond the well-documented role in G1/S transition, mitotic regulation by E2F has also been reported. Proper mitotic progression is monitored by the spindle assembly checkpoint (SAC). The SAC ensures bipolar separation of chromosomes and thus prevents aneuploidy. There are limited reports on the regulation of the SAC by E2F. Our previous work identified the SAC protein Cdc20 as a novel transcriptional regulator of the mitotic ubiquitin carrier protein UbcH10. However, none of the Cdc20 transcription complex proteins have any known DNA binding domain. Here we show that an E2F1-DP1 heterodimer is involved in recruitment of the Cdc20 transcription complex to the UBCH10 promoter and in transactivation of the gene. We further show that inactivation of Rb can facilitate this transactivation process. Moreover, this E2F1-mediated regulation of UbcH10 influences mitotic progression. Deregulation of this pathway results in premature anaphase, chromosomal abnormalities, and aneuploidy. We conclude that excess E2F1 due to Rb inactivation recruits the complex of Cdc20 and the anaphase-promoting complex/cyclosome (Cdc20-APC/C) to deregulate the expression of UBCH10, leading to chromosomal instability in cancer cells. PMID:25368385

  11. Deregulation of Rb-E2F1 axis causes chromosomal instability by engaging the transactivation function of Cdc20-anaphase-promoting complex/cyclosome.

    PubMed

    Nath, Somsubhra; Chowdhury, Abhishek; Dey, Sanjib; Roychoudhury, Anirban; Ganguly, Abira; Bhattacharyya, Dibyendu; Roychoudhury, Susanta

    2015-01-01

    The E2F family of transcription factors regulates genes involved in various aspects of the cell cycle. Beyond the well-documented role in G1/S transition, mitotic regulation by E2F has also been reported. Proper mitotic progression is monitored by the spindle assembly checkpoint (SAC). The SAC ensures bipolar separation of chromosomes and thus prevents aneuploidy. There are limited reports on the regulation of the SAC by E2F. Our previous work identified the SAC protein Cdc20 as a novel transcriptional regulator of the mitotic ubiquitin carrier protein UbcH10. However, none of the Cdc20 transcription complex proteins have any known DNA binding domain. Here we show that an E2F1-DP1 heterodimer is involved in recruitment of the Cdc20 transcription complex to the UBCH10 promoter and in transactivation of the gene. We further show that inactivation of Rb can facilitate this transactivation process. Moreover, this E2F1-mediated regulation of UbcH10 influences mitotic progression. Deregulation of this pathway results in premature anaphase, chromosomal abnormalities, and aneuploidy. We conclude that excess E2F1 due to Rb inactivation recruits the complex of Cdc20 and the anaphase-promoting complex/cyclosome (Cdc20-APC/C) to deregulate the expression of UBCH10, leading to chromosomal instability in cancer cells.

  12. Pre-Exposure of Mycobacterium tuberculosis-Infected Macrophages to Crystalline Silica Impairs Control of Bacterial Growth by Deregulating the Balance between Apoptosis and Necrosis

    PubMed Central

    Chávez-Galán, Leslie; Ramon-Luing, Lucero A.; Torre-Bouscoulet, Luis; Pérez-Padilla, Rogelio; Sada-Ovalle, Isabel

    2013-01-01

    Inhalation of crystalline silica (CS) particles increases the risk of pulmonary tuberculosis; however, the precise mechanism through which CS exposure facilitates Mycobacterium tuberculosis (Mtb) infection is unclear. We speculate that macrophage exposure to CS deregulates the cell death pathways that could explain, at least in part, the association observed between exposure to CS and pulmonary tuberculosis. We therefore established an in vitro model in which macrophages were exposed to CS and then infected with Mtb. Expression of surface markers was analyzed by flow cytometry, JNK1/2, ASK1, caspase 9, P-p38, Bcl-2 and Mcl-1 were analyzed by Western blot, and cytokines by ELISA. Our results show that exposure to CS limits macrophage ability to control Mtb growth. Moreover, this exposure reduced the expression of TLR2, Bcl-2 and Mcl-1, but increased that of JNK1 and ASK1 molecules in the macrophages. Finally, when the pre-exposed macrophages were infected with Mtb, the concentrations of TNFα, IL-1β and caspase-9 expression increased. This pro-inflammatory profile of the macrophage unbalanced the apoptosis/necrosis pathway. Taken together, these data suggest that macrophages exposed to CS are sensitized to cell death by MAPK kinase-dependent signaling pathway. Secretion of TNF-α and IL-1β by Mtb-infected macrophages promotes necrosis, and this deregulation of cell death pathways may favor the release of viable bacilli, thus leading to the progression of tuberculosis. PMID:24278357

  13. Deregulated miR-296/S100A4 axis promotes tumor invasion by inducing epithelial-mesenchymal transition in human ovarian cancer

    PubMed Central

    Yan, Wang; Chen, Jiaqi; Chen, Zhaoying; Chen, Huimin

    2016-01-01

    S100A4 represents an important member of the S100 family of small calcium-binding proteins. Increased expression of S100A4 has been observed in chronic inflammatory and autoimmune diseases, such as idiopathic inflammatory myopathies. The majority of studies of S100A4 are focused on cancer research; however, the oncogenic roles of S100A4 in epithelial ovarian cancer (EOC) remain largely unexplored. In this study, S100A4 expression is significantly up-regulated in ovarian cancer and associated with the clinical stage of EOC patients. Attenuation of S100A4 expression results in decreased cell mobility and metastatic capacity, whereas overexpression of S100A4 enhanced the invasive ability of EOC cells. Then by an integrated informatics analysis and luciferase reporter assay, we identify that miR-296 is a critical upstream regulator of S100A4. In addition, deregulated miR-296/S100A4 axis facilitates epithelial-mesenchymal transition (EMT) process as demonstrated by altered expression of EMT-related markers. In conclusion, our study reveals that deregulated miR-296/S100A4 promotes tumor progression in EOC, and provides evidence that miR-296/S100A4 axis-related signaling may represent a potential target for EOC therapy. PMID:27186401

  14. Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment.

    PubMed

    Schumann, Tim; Adhikary, Till; Wortmann, Annika; Finkernagel, Florian; Lieber, Sonja; Schnitzer, Evelyn; Legrand, Nathalie; Schober, Yvonne; Nockher, W Andreas; Toth, Philipp M; Diederich, Wibke E; Nist, Andrea; Stiewe, Thorsten; Wagner, Uwe; Reinartz, Silke; Müller-Brüsselbach, Sabine; Müller, Rolf

    2015-05-30

    The nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a lipid ligand-inducible transcription factor associated with macrophage polarization. However, its function in tumor-associated macrophages (TAMs) has not been investigated to date. Here, we report the PPARβ/δ-regulated transcriptome and cistrome for TAMs from ovarian carcinoma patients. Comparison with monocyte-derived macrophages shows that the vast majority of direct PPARβ/δ target genes are upregulated in TAMs and largely refractory to synthetic agonists, but repressible by inverse agonists. Besides genes with metabolic functions, these include cell type-selective genes associated with immune regulation and tumor progression, e.g., LRP5, CD300A, MAP3K8 and ANGPTL4. This deregulation is not due to increased expression of PPARβ/δ or its enhanced recruitment to target genes. Instead, lipidomic analysis of malignancy-associated ascites revealed high concentrations of polyunsaturated fatty acids, in particular linoleic acid, acting as potent PPARβ/δ agonists in macrophages. These fatty acid ligands accumulate in lipid droplets in TAMs, thereby providing a reservoir of PPARβ/δ ligands. These observations suggest that the deregulation of PPARβ/δ target genes by ligands of the tumor microenvironment contributes to the pro-tumorigenic polarization of ovarian carcinoma TAMs. This conclusion is supported by the association of high ANGPTL4 expression with a shorter relapse-free survival in serous ovarian carcinoma.

  15. 77 FR 53920 - NASA Federal Advisory Committees

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-04

    ... SPACE ADMINISTRATION NASA Federal Advisory Committees AGENCY: National Aeronautics and Space... amended, the National Aeronautics and Space Administration, and in accordance with the Memorandum for the... NASA's Federal advisory committees. NASA's Federal advisory committees have member vacancies from...

  16. Biomass Resources for the Federal Sector

    SciTech Connect

    Not Available

    2005-08-01

    Biomass Resources for the Federal Sector is a fact sheet that explains how biomass resources can be incorporated into the federal sector, and also how they can provide opportunities to meet federal renewable energy goals.

  17. Biomass Resources for the Federal Sector

    SciTech Connect

    R. Robichaud; A. Crawley; and L. Poole: NREL

    2005-09-09

    Biomass Resources for the Federal Sector is a fact sheet that explains how biomass resources can be incorporated into the federal sector, and also how they can provide opportunities to meet federal renewable energy goals.

  18. 75 FR 6433 - Federal Aviation Administration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-09

    ... Federal Aviation Administration Notice of Availability of a Draft Environmental Assessment and Public...: Federal Aviation Administration (FAA), DOT. ACTION: Notice of Availability of a Draft Environmental... Chicago, Illinois. SUMMARY: The Federal Aviation Administration (FAA) proposes to fund, construct,...

  19. 76 FR 2745 - Federal Aviation Administration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-14

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF TRANSPORTATION Federal Aviation Administration Eighty-Fourth Meeting: RTCA Special Committee 159: Global Positioning System (GPS) AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Notice of RTCA Special...

  20. 76 FR 78966 - Federal Aviation Administration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-20

    ... Federal Aviation Administration Approval of Noise Compatibility Program for Kona International Airport at Keahole, Keahole, North Kona, HI AGENCY: Federal Aviation Administration, DOT. ACTION: Notice. SUMMARY: The Federal Aviation Administration (FAA) announces its findings on the noise compatibility...

  1. 78 FR 25337 - Federal Aviation Administration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-30

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF TRANSPORTATION Federal Aviation Administration Agency Information Collection Activities: Requests for Comments; Clearance of Renewed Approval of Information Collection: Operations Specifications AGENCY: Federal...

  2. 77 FR 64837 - Federal Aviation Administration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-23

    ... Federal Aviation Administration Fourth Meeting: RTCA Special Committee 227, Standards of Navigation Performance AGENCY: Federal Aviation Administration (FAA), U.S. Department of Transportation (DOT). ACTION... 15, 2012. Kathy Hitt, Management Analyst, Business Operations Group, Federal Aviation...

  3. 77 FR 74825 - Information Collection: Federal and Non-Federal Financial Assistant Instruments

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-18

    ... Forest Service Information Collection: Federal and Non-Federal Financial Assistant Instruments AGENCY... holidays. SUPPLEMENTARY INFORMATION: Title: Federal and Non-Federal Financial Assistant Instruments. OMB..., financial plan, statement of work, and cooperator's business information. The Forest Service would not...

  4. Federal budget process: An overview

    NASA Astrophysics Data System (ADS)

    Frizzell, Virgil A., Jr.

    Much geophysical research funding originates from the federal government, and many who obtain federal funding consider the executive branch to be its source. In fact, the federal budget results from a complex ballet between the executive and legislative branches. Because it is both little understood and essential to our work, this report will review the fundamentals of the three-year budgetary process.The Constitution assigns the power of the purse to the Congress. Before the 1920s, executive branch agencies and departments submitted their own separate budgets to Congress, and deliberate planning and priority setting was minimal. In 1921 Congress empowered the president to submit an executive branch budget reflecting his priorities for the next fiscal year. Following this protocol, former President Reagan submitted his budget for Fiscal Year 1990 in January, and President Bush outlined his FY'90 priorities in February.

  5. Reluctant partners: Implementing federal policy

    SciTech Connect

    Stoker, R.P.

    1991-01-01

    Reluctant Partners examines how the federal government can secure the cooperation it needs to effect national policy goals whtn the implementation process itself empowers potential adversaries. The current battle over how and where to permanently store the nation's high-level nuclear waste poses one of the greatest challenges to federalism since the Civil War. Authority has been legislatively diffused among the federal government, the states, the counties, and certain affected Indian tribes. The situation also epitomizes the conflict that arises when Congress delegates final decisionmaking authority to the bureaucracy. The book contributes to the body of implementation literature by moving past organizational theory to consider issues of governance and leadership. However, it will disappoint the empiricist who sees an opportunity for the application of a theory go by the boards.

  6. 30 CFR 900.13 - Federal programs and Federal coal exploration programs.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 3 2011-07-01 2011-07-01 false Federal programs and Federal coal exploration... INTRODUCTION § 900.13 Federal programs and Federal coal exploration programs. The rules for each Federal program and Federal coal exploration program are codified below under the assigned part for the...

  7. 30 CFR 900.13 - Federal programs and Federal coal exploration programs.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 3 2012-07-01 2012-07-01 false Federal programs and Federal coal exploration... INTRODUCTION § 900.13 Federal programs and Federal coal exploration programs. The rules for each Federal program and Federal coal exploration program are codified below under the assigned part for the...

  8. 30 CFR 900.13 - Federal programs and Federal coal exploration programs.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 3 2013-07-01 2013-07-01 false Federal programs and Federal coal exploration... INTRODUCTION § 900.13 Federal programs and Federal coal exploration programs. The rules for each Federal program and Federal coal exploration program are codified below under the assigned part for the...

  9. 30 CFR 900.13 - Federal programs and Federal coal exploration programs.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 3 2014-07-01 2014-07-01 false Federal programs and Federal coal exploration... INTRODUCTION § 900.13 Federal programs and Federal coal exploration programs. The rules for each Federal program and Federal coal exploration program are codified below under the assigned part for the...

  10. 30 CFR 900.13 - Federal programs and Federal coal exploration programs.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 3 2010-07-01 2010-07-01 false Federal programs and Federal coal exploration... INTRODUCTION § 900.13 Federal programs and Federal coal exploration programs. The rules for each Federal program and Federal coal exploration program are codified below under the assigned part for the...

  11. Federalization of Education in Chihuahua

    ERIC Educational Resources Information Center

    Marak, Andrae M.

    2005-01-01

    This article examines the politics behind the initial centralization of primary education in Chihuahua, Mexico during the 1920s and 1930s. The article argues that the centralization of primary education was one of many tools used by the federal government to consolidate its power in the wake of the Mexican Revolution (1910-1917) and create a…

  12. New Federal Cost Accounting Regulations

    ERIC Educational Resources Information Center

    Wolff, George J.; Handzo, Joseph J.

    1973-01-01

    Discusses a new set of indirect cost accounting procedures which must be followed by school districts wishing to recover any indirect costs of administering federal grants and contracts. Also discusses the amount of indirect costs that may be recovered, computing indirect costs, classifying project costs, and restricted grants. (Author/DN)

  13. Teacher Leadership: Federal Policy Recommendations

    ERIC Educational Resources Information Center

    Gran, Jackie; Young, Margaret; Broin, Alexandra

    2015-01-01

    This policy brief was developed specifically for federal policymakers, and builds upon the policy recommendations included in "Leading from Every Seat: Empowering Principals to Cultivate Teacher Leadership for School Improvement." The recommendations in this report include the following: (1) Uncover New Leadership Ideas and Seed…

  14. Followership and the Federal Worker.

    ERIC Educational Resources Information Center

    Gilbert, G. Ronald; Hyde, Albert C.

    1988-01-01

    Defines followership in the workplace. Focuses on federal workers and how they compare to workers in other governmental and private sector settings. Identifies eight dimensions of followership: (1) partnership; (2) motivation; (3) competence; (4) sense of humor; (5) dependability; (6) positive working relations; (7) speaking up; and (8) proper…

  15. The Federal Government and Nutrition.

    ERIC Educational Resources Information Center

    Powers, Margaret A.

    1980-01-01

    Both the Department of Agriculture and the Department of Health and Human Services conduct research related to food and human nutrition. Several federal programs supporting nutrition research and education are reviewed. Footnotes provide addresses and ways to obtain more detailed information about nutrition related programs. (JN)

  16. Who Receives Federal Student Aid?

    ERIC Educational Resources Information Center

    College Entrance Examination Board, Washington, DC.

    Information on federal student aid recipients by income, undergraduate and graduate level, and financial dependency status is presented for Pell Grants, campus-based programs, and Guaranteed Student Loans (GSL). Income data are reported for all aid recipients and for financially dependent and independent students for 1983-1984 and for 1976-1977,…

  17. Data Base Development: Federal Programs.

    ERIC Educational Resources Information Center

    Fisk, Dorothy A.; Weiss, Todd D.

    1980-01-01

    Describes the development of a prototype database of federal food, agriculture, and nutrition programs: preliminary work; database design, including the identification of data elements; and data collection and processing. The uses of the database and suggestions for enhancing its future usefulness are discussed. (Author/JD)

  18. The Universities and Federal Regulation.

    ERIC Educational Resources Information Center

    Crowley, John C.

    The impact of increasing federal regulation on American universities is discussed based on an informal survey of senior academic and administrative officials in 13 public and private universities. As government regulation is becoming more intensive and compliance more resource- and time-consuming, government is perceived as having little…

  19. The Federal Bilingual Education Program

    ERIC Educational Resources Information Center

    Rossell, Christine H.

    2000-01-01

    Since the 1960s, the U.S. Department of Education has enthusiastically embraced bilingual education. In this paper, the author evaluates the federal bilingual education program. Based on her studies of the implementation of bilingual education in California, Massachusetts, and New York City, she concludes that the program is of dubious value. She…

  20. Federal Policy and Adolescent AIDS.

    ERIC Educational Resources Information Center

    Wilcox, Brian L.

    1990-01-01

    Maintains that federal policy on adolescent Acquired Immune Deficiency Syndrome health care and research is nonexistent or piecemeal. Despite the work of the Centers for Disease Control, efforts at preventive education are uncoordinated, resulting from the decentralized nature of the public health and education systems, and are hampered by social…

  1. Deregulation of the California electric power industry: An analysis of electric and natural gas corporate mergers and their effect on the California electric power market

    NASA Astrophysics Data System (ADS)

    Hornbuckle, James Dixon

    Deregulation of the electric utility industry in California is moving in a direction that places greater reliance on the market forces of competition. Investor owned utilities (IOU's) are using mergers and acquisitions to improve their ability to compete in this new environment. Two large mergers were proposed in 1996 that could affect the California market. The first is between Enron Corporation, a large power marketer and Portland General Corporation, owner of Portland General Electric. The second is between Pacific Enterprises Inc., owner of Southern California Gas Company, the largest natural gas utility in the U. S., and Enova Corporation, owner of San Diego Gas and Electric Company. Understanding the impact of these mergers on the California electric power market is the focus of this study. This study examines hypotheses dealing with: (1) Merger Strategy, (2) Efficiency, and (3) Market Power. Using the Miles and Snow (1978) typology, I develop a strategic orientation model for the merger participants and their competitors. The results suggest a two-stage strategic orientation: (1) regulated core business stage, where the firms follow a Defender strategy, and (2) unregulated business stage, where the firms follow a Prospector strategy. Further, the results show the mergers are consistent with the strategy of Enron and Pacific Enterprises. Event study methodology, dollar gains/losses and market value weighted returns are used to determine if the mergers support the efficiency hypothesis. The evidence suggests the mergers lead to increased competitive advantage through improved efficiency for the participants. The results also suggest the mergers do not harm the rivals. The results of structural changes made by the California Public Utilities Commission (CPUC) in deregulation of the California market and analysis of the mergers by the CPUC and the Public Utility Commission of Oregon suggest that the exercise of market power is not a significant issue. Finally

  2. Pleiotropic actions of miR-21 highlight the critical role of deregulated stromal microRNAs during colorectal cancer progression.

    PubMed

    Bullock, M D; Pickard, K M; Nielsen, B S; Sayan, A E; Jenei, V; Mellone, M; Mitter, R; Primrose, J N; Thomas, G J; Packham, G K; Mirenzami, A H; Mirnezami, A H

    2013-01-01

    The oncogene microRNA-21 (miRNA; miR-21) is overexpressed in most solid organ tumours; however, a recent examination of stage II colorectal cancer (CRC) specimens suggests this may be a stromal phenomenon and not only a feature of cancer cells. In vitro and in vivo studies show that miR-21 has potent pro-metastatic effects in various malignant carcinoma cell lines. The tumour microenvironment has also been identified as a key actor during the metastatic cascade; however to date the significance of deregulated miR-21 expression within the cancer-associated stroma has not been examined. In the present study, a quantitative RT-PCR-based analysis of laser microdissected tissue confirmed that miR-21 expression is associated with a four-fold mean increase in CRC stroma compared with normal tissue. In situ hybridisation using locked nucleic acid probes localised miR-21 expression predominantly to fibroblasts within tumour-associated stroma. To study the molecular and biological impact of deregulated stromal miR-21 in CRC, stable ectopic expression was induced in immortalised fibroblasts. This resulted in upregulated α-smooth muscle actin expression implying miR-21 overexpression is driving the fibroblast-to-myofibroblast transdifferentiation. Conditioned medium from miR-21-overexpressing fibroblasts protected CRC cells from oxaliplatin-induced apoptosis and increased their proliferative capacity. 3D organotypic co-cultures containing fibroblasts and CRC cells revealed that ectopic stromal miR-21 expression was associated with increased epithelial invasiveness. Reversion-inducing cysteine-rich protein with kazal motifs, an inhibitor of matrix-remodelling enzyme MMP2, was significantly downregulated by ectopic miR-21 in established and primary colorectal fibroblasts with a reciprocal rise in MMP2 activity. Inhibition of MMP2 abrogated the invasion-promoting effects of ectopic miR-21. This data, which characterises a novel pro-metastatic mechanism mediated by miR-21 in the

  3. Diverse effects of RacV12 on cell transformation by Raf: partial inhibition of morphological transformation versus deregulation of cell cycle control.

    PubMed

    Kerkhoff, Eugen; Leberfinger, Cornelia B; Schmidt, Gudula; Aktories, Klaus; Rapp, Ulf R

    2002-04-01

    Activated Raf kinases and Rac GTPases were shown to cooperate in the oncogenic transformation of fibroblasts, which is characterised by the disassembly of the cellular actin cytoskeleton, a nearly complete loss of focal adhesion complexes and deregulated cell proliferation. This is surprising since the Rac GTPase induces actin structures and the adhesion of suspended cells to extracellular matrix proteins. NIH 3T3 cells expressing a hydroxytamoxifen-inducible oncogenic c-Raf-1-oestrogen receptor fusion protein (c-Raf-1-BxB-ER, N-BxB-ER cells) undergo morphological transformation upon stimulation of the Raf kinase. We show that treatment with the Rac, Rho and Cdc42 activating Escherichia coli toxin CNF1 or coexpression of an activated RacV12 mutant partially inhibits and reverses the disassembly of cellular actin structures and focal adhesion complexes by oncogenic Raf. Activation of the Rac GTPase restores actin structures and focal adhesion complexes at the cellular boundary, leading to spreading of the otherwise spindle-shaped Raf-transformed cells. Actin stress fibres, however, which are regulated by the function of the Rho GTPase, are disassembled by oncogenic Raf even in the presence of activated Rac and Rho. With respect to the RacV12-mediated spreading of Raf-transformed cells, we postulate an anti-oncogenic function of the activated Rac. Another feature of cell transformation is the deregulation of cell cycle control. NIH 3T3 cells expressing high levels of the c-Raf-1-BxB-ER protein undergo a cell cycle arrest upon stimulation of the oncogenic Raf kinase. Our results show that in N-BxB-ER-RacV12 cells the expression of the activated RacV12 mediates cell proliferation in the presence of high-intensity Raf signals and high levels of the Cdk inhibitor p21(Cip1). These results indicate a pro-oncogenic function of the Rac GTPase with respect to the deregulation of cell cycle control.

  4. 40 CFR 1508.12 - Federal agency.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 32 2010-07-01 2010-07-01 false Federal agency. 1508.12 Section 1508.12 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY TERMINOLOGY AND INDEX § 1508.12 Federal agency. Federal agency means all agencies of the Federal Government. It does not mean the Congress,...

  5. 40 CFR 1508.12 - Federal agency.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 34 2012-07-01 2012-07-01 false Federal agency. 1508.12 Section 1508.12 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY TERMINOLOGY AND INDEX § 1508.12 Federal agency. Federal agency means all agencies of the Federal Government. It does not mean the Congress,...

  6. 40 CFR 1508.12 - Federal agency.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 34 2013-07-01 2013-07-01 false Federal agency. 1508.12 Section 1508.12 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY TERMINOLOGY AND INDEX § 1508.12 Federal agency. Federal agency means all agencies of the Federal Government. It does not mean the Congress,...

  7. 40 CFR 1508.12 - Federal agency.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 33 2011-07-01 2011-07-01 false Federal agency. 1508.12 Section 1508.12 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY TERMINOLOGY AND INDEX § 1508.12 Federal agency. Federal agency means all agencies of the Federal Government. It does not mean the Congress,...

  8. Federal Management of Indian Timber lands

    ERIC Educational Resources Information Center

    Nafziger, Rich

    1976-01-01

    The relationship between American Indian timber lands and the Federal Government is discussed in terms of: (1) the economic importance of Indian timber; (2) the trust responsibility of the Federal Government; (3) the management responsibilities of the Federal Government as legislated by Congress; (4) the adequacy of Federal management of Indian…

  9. 1 CFR 11.2 - Federal Register.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... monthly Federal Register Index, and the monthly LSA (List of CFR Sections Affected) is $808 per year for... 1 General Provisions 1 2012-01-01 2012-01-01 false Federal Register. 11.2 Section 11.2 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER AVAILABILITY OF OFFICE OF THE FEDERAL...

  10. 1 CFR 11.2 - Federal Register.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... monthly Federal Register Index, and the monthly LSA (List of CFR Sections Affected) is $808 per year for... 1 General Provisions 1 2013-01-01 2012-01-01 true Federal Register. 11.2 Section 11.2 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER AVAILABILITY OF OFFICE OF THE FEDERAL...

  11. 1 CFR 11.2 - Federal Register.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... monthly Federal Register Index, and the monthly LSA (List of CFR Sections Affected) is $808 per year for... 1 General Provisions 1 2014-01-01 2012-01-01 true Federal Register. 11.2 Section 11.2 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER AVAILABILITY OF OFFICE OF THE FEDERAL...

  12. 14 CFR Special Federal Aviation... - 2

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 2 2011-01-01 2011-01-01 false 2 Federal Special Federal Aviation Regulation No. 100 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRMEN CERTIFICATION: AIRMEN OTHER THAN FLIGHT CREWMEMBERS Special Federal Aviation Regulation...

  13. 14 CFR Special Federal Aviation... - 2

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false 2 Federal Special Federal Aviation Regulation No. 50 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... REQUIREMENTS: DOMESTIC, FLAG, AND SUPPLEMENTAL OPERATIONS Special Federal Aviation Regulation No....

  14. 14 CFR Special Federal Aviation... - 2

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false 2 Federal Special Federal Aviation Regulation No. 50 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... REQUIREMENTS: DOMESTIC, FLAG, AND SUPPLEMENTAL OPERATIONS Special Federal Aviation Regulation No....

  15. 14 CFR Special Federal Aviation... - 2

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 2 2012-01-01 2012-01-01 false 2 Federal Special Federal Aviation Regulation No. 100 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRMEN CERTIFICATION: AIRMEN OTHER THAN FLIGHT CREWMEMBERS Special Federal Aviation Regulation...

  16. 14 CFR Special Federal Aviation... - 2

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 2 2013-01-01 2013-01-01 false 2 Federal Special Federal Aviation Regulation No. 100 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... Federal Aviation Regulation No. 100-2 Editorial Note: For the text of SFAR No. 100-2, see part 61 of...

  17. 14 CFR Special Federal Aviation... - 2

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 2 2014-01-01 2014-01-01 false 2 Federal Special Federal Aviation Regulation No. 100 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... Federal Aviation Regulation No. 100-2 Editorial Note: For the text of SFAR No. 100-2, see part 61 of...

  18. 14 CFR Special Federal Aviation... - 2

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 2 2011-01-01 2011-01-01 false 2 Federal Special Federal Aviation Regulation No. 100 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRMEN CERTIFICATION: FLIGHT CREWMEMBERS OTHER THAN PILOTS Special Federal Aviation Regulation...

  19. 14 CFR Special Federal Aviation... - 2

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false 2 Federal Special Federal Aviation Regulation No. 50 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... REQUIREMENTS: DOMESTIC, FLAG, AND SUPPLEMENTAL OPERATIONS Special Federal Aviation Regulation No....

  20. 14 CFR Special Federal Aviation... - 1

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false 1 Federal Special Federal Aviation Regulation No. 100 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRMEN CERTIFICATION: AIRMEN OTHER THAN FLIGHT CREWMEMBERS Special Federal Aviation Regulation...

  1. 14 CFR Special Federal Aviation... - 2

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 2 2012-01-01 2012-01-01 false 2 Federal Special Federal Aviation Regulation No. 100 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRMEN CERTIFICATION: FLIGHT CREWMEMBERS OTHER THAN PILOTS Special Federal Aviation Regulation...

  2. 14 CFR Special Federal Aviation... - 2

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false 2 Federal Special Federal Aviation Regulation No. 50 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... REQUIREMENTS: DOMESTIC, FLAG, AND SUPPLEMENTAL OPERATIONS Special Federal Aviation Regulation No....

  3. 14 CFR Special Federal Aviation... - 2

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 3 2012-01-01 2012-01-01 false 2 Federal Special Federal Aviation Regulation No. 50 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... Federal Aviation Regulation No. 50-2 Editorial Note: For the text of SFAR No. 50-2, see part 91 of...

  4. 14 CFR Special Federal Aviation... - 2

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false 2 Federal Special Federal Aviation Regulation No. 50 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... REQUIREMENTS: DOMESTIC, FLAG, AND SUPPLEMENTAL OPERATIONS Special Federal Aviation Regulation No....

  5. 14 CFR Special Federal Aviation... - 1

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false 1 Federal Special Federal Aviation Regulation No. 100 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) AIRMEN CERTIFICATION: FLIGHT CREWMEMBERS OTHER THAN PILOTS Special Federal Aviation Regulation...

  6. 14 CFR Special Federal Aviation... - 2

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 3 2013-01-01 2013-01-01 false 2 Federal Special Federal Aviation Regulation No. 50 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... Federal Aviation Regulation No. 50-2 Editorial Note: For the text of SFAR No. 50-2, see part 91 of...

  7. 14 CFR Special Federal Aviation... - 2

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false 2 Federal Special Federal Aviation Regulation No. 50 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... Federal Aviation Regulation No. 50-2 Editorial Note: For the text of SFAR No. 50-2, see part 91 of...

  8. 14 CFR Special Federal Aviation... - 2

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 3 2014-01-01 2014-01-01 false 2 Federal Special Federal Aviation Regulation No. 50 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... Federal Aviation Regulation No. 50-2 Editorial Note: For the text of SFAR No. 50-2, see part 91 of...

  9. 14 CFR Special Federal Aviation... - 2

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false 2 Federal Special Federal Aviation Regulation No. 50 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... Federal Aviation Regulation No. 50-2 Editorial Note: For the text of SFAR No. 50-2, see part 91 of...

  10. 1 CFR 11.2 - Federal Register.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... monthly Federal Register Index, and the monthly LSA (List of CFR Sections Affected) is $808 per year for... 1 General Provisions 1 2010-01-01 2010-01-01 false Federal Register. 11.2 Section 11.2 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER AVAILABILITY OF OFFICE OF THE FEDERAL...

  11. 1 CFR 11.2 - Federal Register.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... monthly Federal Register Index, and the monthly LSA (List of CFR Sections Affected) is $808 per year for... 1 General Provisions 1 2011-01-01 2011-01-01 false Federal Register. 11.2 Section 11.2 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER AVAILABILITY OF OFFICE OF THE FEDERAL...

  12. High Level Architecture (HLA) federation with Umbra and OPNET federates.

    SciTech Connect

    Oppel, Fred John III; Hart, Brian; Van Leeuwen, Brian P.

    2004-03-01

    Network-centric systems that depend on mobile wireless ad hoc networks for their information exchange require detailed analysis to support their development. In many cases, this critical analysis is best provided with high-fidelity system simulations that include the effects of network architectures and protocols. In this research, we developed a high-fidelity system simulation capability using an HLA federation. The HLA federation, consisting of the Umbra system simulator and OPNET Modeler network simulator, provides a means for the system simulator to both affect, and be affected by, events in the network simulator. Advances are also made in increasing the fidelity of the wireless communication channel and reducing simulation run-time with a dead reckoning capability. A simulation experiment is included to demonstrate the developed modeling and simulation capability.

  13. Green Roofs: Federal Energy Management Program (FEMP) Federal Technology Alert

    SciTech Connect

    Scholz-Barth, K.; Tanner, S.

    2004-09-01

    In a ''green roof,'' a layer of vegetation (e.g., a roof garden) covers the surface of a roof to provide shade, cooler indoor and outdoor temperatures, and effective storm-water management to reduce runoff. The main components are waterproofing, soil, and plants. There are two basic kinds: intensive and extensive. An intensive green roof often features large shrubs and trees, and it can be expensive to install and maintain. An extensive green roof features shallow soil and low-growing, horizontally spreading plants that can thrive in the alpine conditions of many rooftops. These plants do not require a lot of water or soil, and they can tolerate a significant amount of exposure to the sun and wind. This Federal Technology Alert focuses on the benefits, design, and implementation of extensive green roofs and includes criteria for their use on federal facilities.

  14. Advanced Gas Turbine (AGT) powertrain system development for automotive applications

    NASA Technical Reports Server (NTRS)

    1981-01-01

    Compressor development, turbine, combustion, regenerator system, gearbox/transmission, ceramic material and component development, foil gas bearings, bearings and seals, rotor dynamics development, and controls and accessories are discussed.

  15. Advanced Gas Turbine (AGT) powertrain system development for automotive applications

    NASA Technical Reports Server (NTRS)

    1984-01-01

    Rotor dynamic instability investigations were conducted. Forward ball bearing hydraulic mount configurations were tested with little effect. Trial assembly of S/N 002 ceramic engine was initiated. Impeller design activities were completed on the straight line element (SLE) blade definition to address near-net-shape powder metal die forging. Performance characteristics of the Baseline Test 2A impeller were closely preserved. The modified blading design has been released for tooling procurement. Developmental testing of the diffusion flame combustor (DFC) for initial use in the S/N 002 2100 F ceramic structures engine was completed. A natural gas slave preheater was designed and fabricated. Preliminary regenerator static seal rig testing showed a significant reduction in leakage and sensitivity to stack height. Ceramic screening tests were completed and two complete sets of ceramic static structures were qualified for engine testing. Efforts on rotor dynamics development to resolve subsynchronous motion were continued.

  16. Advanced Gas Turbine (AGT) power-train system development

    NASA Technical Reports Server (NTRS)

    Helms, H. E.; Johnson, R. A.; Gibson, R. K.

    1982-01-01

    Technical work on the design and component testing of a 74.5 kW (100 hp) advanced automotive gas turbine is described. Selected component ceramic component design, and procurement were tested. Compressor tests of a modified rotor showed high speed performance improvement over previous rotor designs; efficiency improved by 2.5%, corrected flow by 4.6%, and pressure ratio by 11.6% at 100% speed. The aerodynamic design is completed for both the gasifier and power turbines. Ceramic (silicon carbide) gasifier rotors were spin tested to failure. Improving strengths is indicated by burst speeds and the group of five rotors failed at speeds between 104% and 116% of engine rated speed. The emission results from combustor testing showed NOx levels to be nearly one order of magnitude lower than with previous designs. A one piece ceramic exhaust duct/regenerator seal platform is designed with acceptable low stress levels.

  17. Surface operator, bubbling Calabi-Yau and AGT relation

    NASA Astrophysics Data System (ADS)

    Taki, Masato

    2011-07-01

    Surface operators in mathcal{N} = 2 four-dimensional gauge theories are interesting half-BPS objects. These operators inherit the connection of gauge theory with the Liouville conformal field theory, which was discovered by Alday, Gaiotto and Tachikawa. Moreover it has been proposed that toric branes in the A-model topological strings lead to surface operators via the geometric engineering. We analyze the surface operators by making good use of topological string theory. Starting from this point of view, we propose that the wave-function behavior of the topological open string amplitudes geometrically engineers the surface operator partition functions and the Gaiotto curves of corresponding gauge theories. We then study a peculiar feature that the surface operator corresponds to the insertion of the degenerate fields in the conformal field theory side. We show that this aspect can be realized as the geometric transition in topological string theory, and the insertion of a surface operator leads to the bubbling of the toric Calabi-Yau geometry.

  18. Advanced Gas Turbine (AGT): Power-train system development

    NASA Technical Reports Server (NTRS)

    Helms, H. E.; Johnson, R. A.; Gibson, R. K.; Smith, L. B.

    1983-01-01

    Technical work on the design and effort leading to the testing of a 74.5 kW (100 hp) automotive gas turbine is described. The general effort was concentrated on building an engine for test starting in July. The buildup progressed with only routine problems and the engine was delivered to the test stand 9 July. In addition to the engine build effort, work continued in selected component areas. Ceramic turbine parts were built and tested. Burst tests of ceramic rotors show strengths are approaching that achieved in test bars; proof testing is required for acceptable strength ceramic vanes. Over 25 hours was accumulated on the combustor rig in three test modes: pilot nozzle only, start nozzle, and main nozzle operation. Satisfactory ignition was achieved for a wide range of starting speeds and the lean blowout limit was as low as 0.06 kg/b (0.14 lb/hr). Lean blowout was more a function of nozzle atomization than fuel/air ratio. A variety of cycle points were tested. Transition from start nozzle flow to main nozzle flow was done manually without difficulty. Regenerator parts were qualification tested without incident and the parts were assembled on schedule. Rig based performance matched first build requirements. Repeated failures in the harmonic drive gearbox during rig testing resulted in that concept being abandoned for an alternate scheme.

  19. Advanced Gas Turbine (AGT) powertrain system development for automotive applications

    NASA Technical Reports Server (NTRS)

    1981-01-01

    Preliminary layouts were made for the exhaust system, air induction system, and battery installation. Points of interference were identified and resolved by altering either the vehicle or engine designs. An engine general arrangement evolved to meet the vehicle engine compartment constraints while minimizing the duct pressure losses and the heat rejection. A power transfer system (between gasifier and power turbines) was developed to maintain nearly constant temperatures throughout the entire range of engine operation. An advanced four speed automatic transmission was selected to be used with the engine. Performance calculations show improvements in component efficiencies and an increase in fuel economy. A single stage centrifugal compressor design was completed and released for procurement. Gasifier turbine, power turbine, combustor, generator, secondary systems, materials, controls, and transmission development are reported.

  20. 78 FR 14776 - Federal Perkins Loan, Federal Work-Study, and Federal Supplemental Educational Opportunity Grant...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-07

    ...; 2013-2014 Award Year Deadline Dates AGENCY: Federal Student Aid, Department of Education. ACTION... institutions to make low-interest, long-term loans to needy undergraduate and graduate students to help pay for... students to help pay for their education and to involve the students in community service activities....

  1. Physical and functional interaction of the proto-oncogene EVI1 and tumor suppressor gene HIC1 deregulates Bcl-xL mediated block in apoptosis.

    PubMed

    Pradhan, Anjan Kumar; Halder, Arundhati; Chakraborty, Soumen

    2014-08-01

    Ecotropic viral integration site 1 was originally identified as a retroviral integration site in murine leukemias. Several studies have established ecotropic viral integration site 1 as both a transcription factor and an interacting partner that presumably regulates gene expression. Using coimmunoprecipitation and fluorescence resonance energy transfer analysis, we found that the N-terminal domain of hypermethylated in cancer 1 interacts with the proximal set of zinc fingers of ecotropic viral integration site 1. This interaction not only abolishes the DNA binding activity of ecotropic viral integration site 1 but also disrupts the transcriptional activity of an anti-apoptotic gene promoter selectively targeted by ecotropic viral integration site 1. By using flow cytometry and western blotting, here we show that hypermethylated in cancer 1 can deregulate ecotropic viral integration site 1-mediated blockage of apoptosis. We hypothesize that therapeutic upregulation of hypermethylated in cancer 1 may provide an important means of targeting ecotropic viral integration site 1-positive cancers.

  2. Differential antioxidant defense and detoxification mechanisms in photodynamically stressed rice plants treated with the deregulators of porphyrin biosynthesis, 5-aminolevulinic acid and oxyfluorfen

    SciTech Connect

    Phung, Thu-Ha; Jung, Sunyo

    2015-04-03

    This study focuses on differential molecular mechanisms of antioxidant and detoxification systems in rice plants under two different types of photodynamic stress imposed by porphyrin deregulators, 5-aminolevulinic acid (ALA) and oxyfluorfen (OF). The ALA-treated plants with white necrosis exhibited a greater decrease in photochemical quantum efficiency, F{sub v}/F{sub m}, as well as a greater increase in activity of superoxide dismutase, compared to the OF-treated plants. By contrast, the brown necrosis in OF-treated plants resulted in not only more widely dispersed H{sub 2}O{sub 2} production and greater increases in H{sub 2}O{sub 2}-decomposing enzymes, catalase and peroxidase, but also lower ascorbate redox state. In addition, ALA- and OF-treated plants markedly up-regulated transcript levels of genes involved in detoxification processes including transport and movement, cellular homeostasis, and xenobiotic conjugation, with prominent up-regulation of serine/threonine kinase and chaperone only in ALA-treated plants. Our results demonstrate that different photodynamic stress imposed by ALA and OF developed differential actions of antioxidant enzymes and detoxification. Particularly, detoxification system may play potential roles in plant protection against photodynamic stress imposed by porphyrin deregulators, thereby contributing to alleviation of photodynamic damage. - Highlights: • We employ two different types of photodynamic stress, white and brown necrosis. • We examine molecular mechanisms of antioxidative and detoxification systems. • ALA and OF develop differential actions of antioxidant and detoxification systems. • Coordinated mechanism of antioxidants and detoxification works against toxic ROS. • Detoxification system plays critical roles in protection against photodynamic stress.

  3. Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water.

    PubMed

    Muñoz, Alexandra; Chervona, Yana; Hall, Megan; Kluz, Thomas; Gamble, Mary V; Costa, Max

    2015-05-01

    Arsenic contamination of drinking water occurs globally and is associated with numerous diseases including skin, lung and bladder cancers, and cardiovascular disease. Recent research indicates that arsenic may be an endocrine disruptor. This study was conducted to evaluate the nature of gene expression changes among males and females exposed to arsenic contaminated water in Bangladesh at high and low doses. Twenty-nine (55% male) Bangladeshi adults with water arsenic exposure ranging from 50 to 1000 μg/L were selected from the Folic Acid Creatinine Trial. RNA was extracted from peripheral blood mononuclear cells for gene expression profiling using Affymetrix 1.0 ST arrays. Differentially expressed genes were assessed between high and low exposure groups for males and females separately and findings were validated using quantitative real-time PCR. There were 534 and 645 differentially expressed genes (p<0.05) in the peripheral blood mononuclear cells of males and females, respectively, when high and low water arsenic exposure groups were compared. Only 43 genes overlapped between the two sexes, with 29 changing in opposite directions. Despite the difference in gene sets both males and females exhibited common biological changes including deregulation of 17β-hydroxysteroid dehydrogenase enzymes, deregulation of genes downstream of Sp1 (specificity protein 1) transcription factor, and prediction of estrogen receptor alpha as a key hub in cardiovascular networks. Arsenic-exposed adults exhibit sex-specific gene expression profiles that implicate involvement of the endocrine system. Due to arsenic's possible role as an endocrine disruptor, exposure thresholds for arsenic may require different parameters for males and females. PMID:25759245

  4. Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water1

    PubMed Central

    Muñoz, Alexandra; Chervona, Yana; Hall, Megan; Kluz, Thomas; Gamble, Mary V.; Costa, Max

    2015-01-01

    Arsenic contamination of drinking water occurs globally and is associated with numerous diseases including skin, lung and bladder cancers, and cardiovascular disease. Recent research indicates that arsenic may be an endocrine disruptor. This study was conducted to evaluate the nature of gene expression changes among males and females exposed to arsenic contaminated water in Bangladesh at high and low doses. Twenty-nine (55% male) Bangladeshi adults with water arsenic exposure ranging from 50–1000 µg/ L were selected from the Folic Acid Creatinine Trial. RNA was extracted from peripheral blood mononuclear cells for gene expression profiling using Affymetrix 1.0 ST arrays. Differentially expressed genes were assessed between high and low exposure groups for males and females separately and findings were validated using quantitative real-time PCR. There were 534 and 645 differentially expressed genes (p<0.05) in the peripheral blood mononuclear cells of males and females, respectively, when high and low water arsenic exposure groups were compared. Only 43 genes overlapped between the two sexes, with 29 changing in opposite directions. Despite the difference in gene sets both males and females exhibited common biological changes including deregulation of 17β-hydroxysteroid dehydrogenase enzymes, deregulation of genes downstream of Sp1 (specificity protein 1) transcription factor, and prediction of estrogen receptor alpha as a key hub in cardiovascular networks. Arsenic-exposed adults exhibit sex-specific gene expression profiles that implicate involvement of the endocrine system. Due to arsenic’s possible role as an endocrine disruptor, exposure thresholds for arsenic may require different parameters for males and females. PMID:25759245

  5. Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water.

    PubMed

    Muñoz, Alexandra; Chervona, Yana; Hall, Megan; Kluz, Thomas; Gamble, Mary V; Costa, Max

    2015-05-01

    Arsenic contamination of drinking water occurs globally and is associated with numerous diseases including skin, lung and bladder cancers, and cardiovascular disease. Recent research indicates that arsenic may be an endocrine disruptor. This study was conducted to evaluate the nature of gene expression changes among males and females exposed to arsenic contaminated water in Bangladesh at high and low doses. Twenty-nine (55% male) Bangladeshi adults with water arsenic exposure ranging from 50 to 1000 μg/L were selected from the Folic Acid Creatinine Trial. RNA was extracted from peripheral blood mononuclear cells for gene expression profiling using Affymetrix 1.0 ST arrays. Differentially expressed genes were assessed between high and low exposure groups for males and females separately and findings were validated using quantitative real-time PCR. There were 534 and 645 differentially expressed genes (p<0.05) in the peripheral blood mononuclear cells of males and females, respectively, when high and low water arsenic exposure groups were compared. Only 43 genes overlapped between the two sexes, with 29 changing in opposite directions. Despite the difference in gene sets both males and females exhibited common biological changes including deregulation of 17β-hydroxysteroid dehydrogenase enzymes, deregulation of genes downstream of Sp1 (specificity protein 1) transcription factor, and prediction of estrogen receptor alpha as a key hub in cardiovascular networks. Arsenic-exposed adults exhibit sex-specific gene expression profiles that implicate involvement of the endocrine system. Due to arsenic's possible role as an endocrine disruptor, exposure thresholds for arsenic may require different parameters for males and females.

  6. Correlation Network Analysis Reveals Relationships between MicroRNAs, Transcription Factor T-bet, and Deregulated Cytokine/Chemokine-Receptor Network in Pulmonary Sarcoidosis

    PubMed Central

    Dyskova, Tereza; Fillerova, Regina; Novosad, Tomas; Kudelka, Milos; Zurkova, Monika; Gajdos, Petr; Kolek, Vitezslav; Kriegova, Eva

    2015-01-01

    Sarcoidosis is an inflammatory granulomatous disease with unknown etiology driven by cytokines and chemokines. There is limited information regarding the regulation of cytokine/chemokine-receptor network in bronchoalveolar lavage (BAL) cells in pulmonary sarcoidosis, suggesting contribution of miRNAs and transcription factors. We therefore investigated gene expression of 25 inflammation-related miRNAs, 27 cytokines/chemokines/receptors, and a Th1-transcription factor T-bet in unseparated BAL cells obtained from 48 sarcoidosis patients and 14 control subjects using quantitative RT-PCR. We then examined both miRNA-mRNA expressions to enrich relevant relationships. This first study on miRNAs in sarcoid BAL cells detected deregulation of miR-146a, miR-150, miR-202, miR-204, and miR-222 expression comparing to controls. Subanalysis revealed higher number of miR-155, let-7c transcripts in progressing (n = 20) comparing to regressing (n = 28) disease as assessed by 2-year follow-up. Correlation network analysis revealed relationships between microRNAs, transcription factor T-bet, and deregulated cytokine/chemokine-receptor network in sarcoid BAL cells. Furthermore, T-bet showed more pronounced regulatory capability to sarcoidosis-associated cytokines/chemokines/receptors than miRNAs, which may function rather as “fine-tuners” of cytokine/chemokine expression. Our correlation network study implies contribution of both microRNAs and Th1-transcription factor T-bet to the regulation of cytokine/chemokine-receptor network in BAL cells in sarcoidosis. Functional studies are needed to confirm biological relevance of the obtained relationships. PMID:26696750

  7. Deregulation of miRNA-181c potentially contributes to the pathogenesis of AD by targeting collapsin response mediator protein 2 in mice.

    PubMed

    Zhou, Huimin; Zhang, Rui; Lu, Kang; Yu, Wenjun; Xie, Bing; Cui, Dongsheng; Jiang, Lei; Zhang, Qingfu; Xu, Shunjiang

    2016-08-15

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is usually accompanied by abnormal gene expression. The 20 to 25 nucleotide (nt) tiny regulators, known as micro ribonucleic acids (miRNAs), have been found to play important roles in the etiology and pathogenesis of various biological processes. The purpose of the current study was to identify the aberrant expression of microRNAs in the hippocampus of an AD mouse model and to investigate its potential role during the progression of AD. The results from microarray analysis showed that several miRNAs were deregulated in the hippocampus tissue of SAMP8 mice compared to SAMR1 mice. Among the deregulated miRNAs, a significant decrease in miR-181c was validated by quantitative real-time PCR. Bioinformatic analysis revealed that miR-181c might be involved in the regulation of axon guidance, MAPK signaling, dorso-ventral axis formation and long-term depression. Moreover, the results of a luciferase activity assay, western blot analysis and immunofluorescent staining showed that over-expression of miR-181c targets the 3'-untranslated region (3'-UTR) of collapsin response mediator protein 2 (crmp2) through its binding sites and down-regulates crmp2 protein abundance at the post-transcriptional level. Taken together, these findings suggested that crmp2 is a target of miR-181c and that the abnormally low expression of miR-181c in the hippocampus of SAMP8 mice could lead to an increase of the crmp2 protein level in AD mice, which might potentially play a role in the pathogenesis of Alzheimer's disease. PMID:27423553

  8. The expression of miR-21 and miR-143 is deregulated by the HPV16 E7 oncoprotein and 17β-estradiol.

    PubMed

    Gómez-Gómez, Yazmín; Organista-Nava, Jorge; Ocadiz-Delgado, Rodolfo; García-Villa, Enrique; Leyva-Vazquez, Marco Antonio; Illades-Aguiar, Berenice; Lambert, Paul F; García-Carrancá, Alejandro; Gariglio, Patricio

    2016-08-01

    MicroRNAs (miRNAs) are a class of non-coding RNAs that negatively regulate their target mRNAs at a posttranscriptional level, thereby affecting crucial processes in cancer development. However, little is known about the molecular events that control expression of miRNAs in cervical cancer (CC). HPV16 E7 oncoprotein in conjunction with estrogen are sufficient to produce high grade cervical dysplasia and invasive cervical malignancies in a mouse model. In the present study, we determined the potential role that the E7 oncoprotein and 17β-estradiol (E2) play in the deregulation of miR-21 and miR-143 expression levels by these two risk factors. We found that, while the expression of miR-21 was upregulated and the expression of miR-143 was downregulated by the HPV16 E7 oncoprotein in vivo, and in vitro and that E2 treatment is also implicated in the deregulation of these important miRNAs in vivo. Sustained upregulation of miR-21 resulted in suppression of PTEN expression, and repression of miR-143 increased the mRNA and protein levels from Bcl-2. These results suggested that HPV type 16 E7 oncoprotein and E2 play an important role in regulating miR-21 and miR-143 expression. We have observed similar results in CC patients containing HPV16 sequences, suggesting that these miRNAs could serve as diagnostic biomarkers in CC. The present study highlights the roles of miRNAs in cervical tissue and implicates these important molecules in cervical carcinogenesis. PMID:27278606

  9. Findability of Federal Research Data

    NASA Astrophysics Data System (ADS)

    Hourcle, J. A.

    2013-12-01

    Findability of Federal Research Data Although many of the federal agencies have been providing access to scientific research data for years if not decades, the findability of the data has been quite lacking. Many discipline-wide efforts have been made in the big science communities, such as PDS for planetary science and the VOs in night time astronomy and heliophysics, but there is a lack of single entry point for someone looking for data. The science.gov website contains links to many of these big-science search systems, but doesn't differentiate between links to science quality data and websites or browse products, making it more difficult to search specifically for data. The data.gov website is a useful repository for PIs of small science data to stash their data, particularly as it allows for interested parties to interact with tabular data. Unfortunately, as each group thinks of their data differently, much of what's now in the system is a mess; collections of data being tracked as individual records with no relationships between them. Big science projects also get tracked as single records, potentially with only a single record for missions with multiple instruments and significantly different data series. We present recommendations on how to improve the findability of federal research data on data.gov, based on years of working on the Virtual Solar Observatory and withing the science informatics community.

  10. 77 FR 47374 - Notice of Proposed Information Collection Requests; Federal Student Aid; William D. Ford Federal...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-08

    ... Notice of Proposed Information Collection Requests; Federal Student Aid; William D. Ford Federal Direct Loan (Direct Loan) Program/ Federal Family Loan (FFEL) Program: Deferment Request Forms AGENCY... William D. Ford Federal Direct Loan (Direct Loan) and Federal Family Education Loan (FFEL) Programs...

  11. 34 CFR 682.501 - Extent of Federal guarantee under the Federal GSL programs.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... (Continued) OFFICE OF POSTSECONDARY EDUCATION, DEPARTMENT OF EDUCATION FEDERAL FAMILY EDUCATION LOAN (FFEL) PROGRAM Federal Guaranteed Student Loan Programs § 682.501 Extent of Federal guarantee under the Federal... guarantee liability on any Federal GSL loan is 100 percent of the unpaid principal balance and, to...

  12. 78 FR 67200 - Federal-State Unemployment Compensation Program: Certifications for 2013 Under the Federal...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-08

    ... Employment and Training Administration Federal-State Unemployment Compensation Program: Certifications for 2013 Under the Federal Unemployment Tax Act AGENCY: Employment and Training Administration. ACTION: Notice. SUMMARY: The Secretary of Labor signed the annual certifications under the Federal...

  13. Federal laboratories for the 21st century

    SciTech Connect

    Gover, J.; Huray, P.G.

    1998-04-01

    Federal laboratories have successfully filled many roles for the public; however, as the 21st Century nears it is time to rethink and reevaluate how Federal laboratories can better support the public and identify new roles for this class of publicly-owned institutions. The productivity of the Federal laboratory system can be increased by making use of public outcome metrics, by benchmarking laboratories, by deploying innovative new governance models, by partnerships of Federal laboratories with universities and companies, and by accelerating the transition of federal laboratories and the agencies that own them into learning organizations. The authors must learn how government-owned laboratories in other countries serve their public. Taiwan`s government laboratory, Industrial Technology Research Institute, has been particularly successful in promoting economic growth. It is time to stop operating Federal laboratories as monopoly institutions; therefore, competition between Federal laboratories must be promoted. Additionally, Federal laboratories capable of addressing emerging 21st century public problems must be identified and given the challenge of serving the public in innovative new ways. Increased investment in case studies of particular programs at Federal laboratories and research on the public utility of a system of Federal laboratories could lead to increased productivity of laboratories. Elimination of risk-averse Federal laboratory and agency bureaucracies would also have dramatic impact on the productivity of the Federal laboratory system. Appropriately used, the US Federal laboratory system offers the US an innovative advantage over other nations.

  14. 78 FR 33092 - Federal Advisory Committee Act; Technological Advisory Council

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-03

    ... From the Federal Register Online via the Government Publishing Office FEDERAL COMMUNICATIONS COMMISSION Federal Advisory Committee Act; Technological Advisory Council AGENCY: Federal Communications..., this notice advises interested persons that the Federal Communications Commission's (FCC)...

  15. 77 FR 70434 - Federal Advisory Committee Act; Technological Advisory Council

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-26

    ... From the Federal Register Online via the Government Publishing Office FEDERAL COMMUNICATIONS COMMISSION Federal Advisory Committee Act; Technological Advisory Council AGENCY: Federal Communications..., this notice advises interested persons that the Federal Communications Commission's (FCC)...

  16. 76 FR 31393 - Federal Acquisition Regulation; Federal Acquisition Circular 2005-52; Introduction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-31

    ... implement Executive Order 13514, Federal Leadership in Environmental, Energy, and Economic Performance, and... specified, all Federal Acquisition Regulation (FAR) ] and other directive material contained in FAC...

  17. Federal government expands compliance initiatives.

    PubMed

    Dugan, J K

    1997-09-01

    In 1995, the Federal government initiated Operation Restore Trust to increase enforcement of fraud and abuse regulations in Medicare and Medicaid programs. With the success of the original initiative, the government is expanding the project to additional states and program areas. The initial scrutiny of home health agencies, nursing homes, hospice care, and durable medical equipment is being expanded to managed care plans and acute care hospitals with an eye toward DRG creep. To manage this increased enforcement activity, healthcare organizations should institute comprehensive corporate compliance programs. Such programs should provide a framework that delineates responsibilities and provides a systematic means to resolve issues in a timely manner. PMID:10170318

  18. Federal government expands compliance initiatives.

    PubMed

    Dugan, J K

    1997-09-01

    In 1995, the Federal government initiated Operation Restore Trust to increase enforcement of fraud and abuse regulations in Medicare and Medicaid programs. With the success of the original initiative, the government is expanding the project to additional states and program areas. The initial scrutiny of home health agencies, nursing homes, hospice care, and durable medical equipment is being expanded to managed care plans and acute care hospitals with an eye toward DRG creep. To manage this increased enforcement activity, healthcare organizations should institute comprehensive corporate compliance programs. Such programs should provide a framework that delineates responsibilities and provides a systematic means to resolve issues in a timely manner.

  19. Federal constraints: earned or unearned?

    PubMed

    Chalkley, D T

    1977-08-01

    The author discusses the evolution of federal constraints on medical, behavioral, and social science research. There has been only one court decision related to behavioral research and none in medical research. The burden of consent procedures can be lightened somewhat by careful consideration of the potential risks and nature of the research; questions are presented that can be used to determine whether constraints apply. The author notes that although there are good reasons for regulations in both behavioral and medical research, the appropriateness of current and proposed constraints is still a matter of debate.

  20. Federal Wind Energy Research Program

    SciTech Connect

    Not Available

    1991-10-01

    The Office of Program Analysis (OPA) undertook an assessment of 55 research projects sponsored by the Federal Wind Energy Research Program. This report summarizes the results of that review. In accordance with statue and policy guidance, the program's research has targeted the sciences of wind turbine dynamics and the development of advanced components and systems. Wind turbine research has focused on atmospheric fluid dynamics, aerodynamics, and structural dynamics. Rating factors including project scientific and technical merit, appropriateness and level of innovation of the technical approach, quality of the project team, productivity, and probable impact on the program's mission. Each project was also given an overall evaluation supported with written comments. 1 fig.

  1. Federal Facility Agreement progress report

    SciTech Connect

    Not Available

    1993-10-01

    The (SRS) Federal Facility Agreement (FFA) was made effective by the US. Environmental Protection Agency Region IV (EPA) on August 16, 1993. To meet the reporting requirements in Section XXV of the Agreement, the FFA Progress Report was developed. The FFA Progress Report is the first of a series of quarterly progress reports to be prepared by the SRS. As such this report describes the information and action taken to September 30, 1993 on the SRS units identified for investigation and remediation in the Agreement. This includes; rubble pits, runoff basins, retention basin, seepage basin, burning pits, H-Area Tank 16, and spill areas.

  2. 75 FR 68010 - Federal Salary Council

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-04

    ... locality pay areas, the coverage of salary surveys, the process of comparing Federal and non-Federal rates... Pay Agent on pay comparison methods, locality pay rates, and locality pay areas and boundaries...

  3. 77 FR 59026 - Federal Salary Council

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-09-25

    ... locality pay areas, the coverage of salary surveys, the process of comparing Federal and non-Federal rates... and boundaries for 2014. The meeting is open to the public. Please contact the Office of...

  4. 7 CFR 275.3 - Federal monitoring.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... participants. Editorial Note: For Federal Register citations affecting § 275.3, see the List of CFR Sections... accordance with program requirements. The Federal reviewer may consolidate the scheduling and conduction...

  5. 23 CFR 750.305 - Federal participation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... materially damaged by vandals. Federal funds shall be limited to the Federal pro-rata share of the fair... advertising or informative content thereon unless the owner can show to the State's satisfaction he has...

  6. Federal Funding for Career and Technical Education.

    ERIC Educational Resources Information Center

    Reese, Susan

    2002-01-01

    Describes how federal funding for vocational education works. Looks at the Perkins Act, Pell Grants, the Workforce Investment Act of 1998, and Temporary Assistance for Needy Families. Addresses the importance of federal funding. (JOW)

  7. 77 FR 3804 - Sunshine Federal Register Notice

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-25

    ... of Certain Types of Nuclear Waste (RIN 3150-AG41) (Tentative) * The schedule for Commission meetings... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Sunshine Federal Register Notice AGENCY HOLDING THE MEETINGS: Nuclear Regulatory Commission,...

  8. 2 CFR 180.950 - Federal agency.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... Grants and Agreements Office of Management and Budget Guidance for Grants and Agreements OFFICE OF MANAGEMENT AND BUDGET GOVERNMENTWIDE GUIDANCE FOR GRANTS AND AGREEMENTS NATIONAL POLICY REQUIREMENTS OMB... Federal agency. Federal agency means any United States executive department, military department,...

  9. 2 CFR 180.950 - Federal agency.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... Grants and Agreements Office of Management and Budget Guidance for Grants and Agreements OFFICE OF MANAGEMENT AND BUDGET GOVERNMENTWIDE GUIDANCE FOR GRANTS AND AGREEMENTS NATIONAL POLICY REQUIREMENTS OMB... Federal agency. Federal agency means any United States executive department, military department,...

  10. About the Federal Energy Management Program

    SciTech Connect

    Richard Kidd

    2009-04-23

    Richard Kidd, Program Manager for the Federal Energy Management Program (FEMP), presents a discussion on FEMP direction and its future role, federal funding trends, future financing trends, and Earth Day observations.

  11. 78 FR 13395 - Federal Aviation Administration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-27

    ... of October 23, 2012 (77 FR 64836) would require placement of fill on submerged lands jointly managed... Federal Aviation Administration Notice of Availability of Draft Alaska National Interest Lands Conservation Act (ANILCA) Section 810 Subsistence Evaluation. AGENCY: Federal Aviation Administration...

  12. Which Efficient Products Must Federal Agencies Buy

    SciTech Connect

    2010-08-24

    Fact sheet prepared by the U.S. Department of Energy (DOE) Federal Energy Management Program (FEMP) to help Federal agencies comply with FEMP Designated, Low Standby Power, ENERGY STAR Qualified, and Water Sense Labeled product purchasing requirements.

  13. 78 FR 65717 - Federal Salary Council

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-01

    ...: The Federal Salary Council meeting originally scheduled for November 5, 2013 (FR Vol. 78, No. 192... locality pay areas, the coverage of salary surveys, the process of comparing Federal and non-Federal rates... and boundaries for 2015. The meeting is open to the public. Please contact the Office of...

  14. Investigate the Federal Agencies for Experiential Spots.

    ERIC Educational Resources Information Center

    Allen, Claudia

    1993-01-01

    Alerts career counselors to thousands of co-op, intern, and summer job opportunities that Central Intelligence Agency and other federal agencies offer each year. Notes that challenge is in locating the right job for the student. Provides information on where to call for information about federal employment, pay scales for federal experiential…

  15. 40 CFR 62.13 - Federal plans.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 9 2013-07-01 2013-07-01 false Federal plans. 62.13 Section 62.13... PROMULGATION OF STATE PLANS FOR DESIGNATED FACILITIES AND POLLUTANTS General Provisions § 62.13 Federal plans. The Federal plans apply to owners and operators of affected facilities that are not covered by an...

  16. 23 CFR 751.17 - Federal participation.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 23 Highways 1 2014-04-01 2014-04-01 false Federal participation. 751.17 Section 751.17 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RIGHT-OF-WAY AND ENVIRONMENT JUNKYARD CONTROL... Interstate and primary highways, the FHWA may approve Federal participation in the costs of applying...

  17. 23 CFR 751.17 - Federal participation.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 23 Highways 1 2013-04-01 2013-04-01 false Federal participation. 751.17 Section 751.17 Highways FEDERAL HIGHWAY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RIGHT-OF-WAY AND ENVIRONMENT JUNKYARD CONTROL... Interstate and primary highways, the FHWA may approve Federal participation in the costs of applying...

  18. Federal Information Sources for Adult Illiteracy.

    ERIC Educational Resources Information Center

    Darby, Christine M.

    This interdisciplinary guide to public policy for adult education has four objectives: (1) to provide both information about the supply of federal information on the topic and assistance with searching federal sources; (2) to build a basic understanding of federally produced information on an interdisciplinary topic; (3) to introduce the…

  19. 10 CFR 961.5 - Federal agencies.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 4 2011-01-01 2011-01-01 false Federal agencies. 961.5 Section 961.5 Energy DEPARTMENT OF ENERGY STANDARD CONTRACT FOR DISPOSAL OF SPENT NUCLEAR FUEL AND/OR HIGH-LEVEL RADIOACTIVE WASTE General § 961.5 Federal agencies. Federal agencies or departments requiring DOE's disposal services for SNF...

  20. 10 CFR 961.5 - Federal agencies.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 4 2014-01-01 2014-01-01 false Federal agencies. 961.5 Section 961.5 Energy DEPARTMENT OF ENERGY STANDARD CONTRACT FOR DISPOSAL OF SPENT NUCLEAR FUEL AND/OR HIGH-LEVEL RADIOACTIVE WASTE General § 961.5 Federal agencies. Federal agencies or departments requiring DOE's disposal services for SNF...

  1. 10 CFR 961.5 - Federal agencies.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 4 2013-01-01 2013-01-01 false Federal agencies. 961.5 Section 961.5 Energy DEPARTMENT OF ENERGY STANDARD CONTRACT FOR DISPOSAL OF SPENT NUCLEAR FUEL AND/OR HIGH-LEVEL RADIOACTIVE WASTE General § 961.5 Federal agencies. Federal agencies or departments requiring DOE's disposal services for SNF...

  2. 10 CFR 961.5 - Federal agencies.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Federal agencies. 961.5 Section 961.5 Energy DEPARTMENT OF ENERGY STANDARD CONTRACT FOR DISPOSAL OF SPENT NUCLEAR FUEL AND/OR HIGH-LEVEL RADIOACTIVE WASTE General § 961.5 Federal agencies. Federal agencies or departments requiring DOE's disposal services for SNF...

  3. 10 CFR 961.5 - Federal agencies.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 4 2012-01-01 2012-01-01 false Federal agencies. 961.5 Section 961.5 Energy DEPARTMENT OF ENERGY STANDARD CONTRACT FOR DISPOSAL OF SPENT NUCLEAR FUEL AND/OR HIGH-LEVEL RADIOACTIVE WASTE General § 961.5 Federal agencies. Federal agencies or departments requiring DOE's disposal services for SNF...

  4. 75 FR 61552 - Federal Railroad Administration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-05

    ... Federal Railroad Administration Notice of Informational Filing In accordance with Section 236.913 of Title 49 of the Code of Federal Regulations (CFR), notice is hereby given that the Federal Railroad Administration (FRA) has received an informational filing from the Northeast Illinois Regional Commuter...

  5. 76 FR 76899 - Federal Acquisition Regulation; Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-09

    ... FR 68039). The final rule amended the Federal Acquisition Regulation (FAR) to revise the definitions..., 2011 (76 FR 68039). The rule amended the Federal Acquisition Regulation (FAR) by revising the...; Correction; FAR Case 2011-014; Docket 2011-0014; Sequence 1] RIN 9000-AM11 Federal Acquisition...

  6. 75 FR 43090 - Federal Acquisition Regulation; Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-23

    ... was published in the Federal Register at 75 FR 38684, July 2, 2010. DATES: Effective Date: July 23... document in the Federal Register of July 2, 2010 (75 FR 38684) amending FAR 52.204-11(d)(10). The amendment... Federal Acquisition Regulation; Correction AGENCY: Department of Defense (DoD), General...

  7. Federal Employment of People with Disabilities

    ERIC Educational Resources Information Center

    Domzal, Christine

    2009-01-01

    The purpose of this paper is to examine the status of employment of people with disabilities in the Federal Government and to make recommendations for improving federal hiring and advancement of employees with disabilities. The paper summarizes the legal authorities and policy guidance, the responsibilities of various federal agencies charged with…

  8. 78 FR 25524 - Federal Aviation Administration

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-01

    ... TRANSPORTATION Federal Aviation Administration Notice of Request To Release Airport Property AGENCY: Federal Aviation Administration (FAA), DOT. ACTION: Notice of Intent to Rule on Request to Release Airport Property..., Airports Compliance Specialist, Federal Aviation Administration, Airports Division, ACE- 610C, 901...

  9. The Federal Role in Postsecondary Education.

    ERIC Educational Resources Information Center

    Hodgkinson, Virginia A.

    The federal role in postsecondary education since 1787 is traced. Attention is directed to the types of indirect federal support toward postsecondary education until the first Higher Education Act of 1965, and the kinds of national priorities served by the current federal role in postsecondary education. Future projections and the implications of…

  10. 76 FR 66754 - Federal Bureau of Prisons

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-27

    ... Federal Bureau of Prisons Notice of Availability of the Record of Decision for Proposed Contract Award to... AGENCY: U.S. Department of Justice, Federal Bureau of Prisons. ACTION: Notice of a Record of Decision. SUMMARY: The U.S. Department of Justice, Federal Bureau of Prisons (BOP) announces the availability of...

  11. Federal Student Aid Annual Report, 2010

    ERIC Educational Resources Information Center

    US Department of Education, 2010

    2010-01-01

    This paper presents the Federal Student Aid Annual Report for 2010. Federal Student Aid experienced an extraordinary year in 2010. The passage and enactment of the Health Care and Education Reconciliation Act of 2010 ushered in sweeping reforms to the federal student financial assistance programs, resulting in tens of billions of dollars in…

  12. Female Offenders in the Federal Correctional System.

    ERIC Educational Resources Information Center

    Foster, Euphesenia

    The illustrated booklet provides a brief history of Federal prisons and of Federal women's prisons. There is statistical information on women prisoners classified by age, race, period of confinement, marital status, type of crime, and judicial district from which the commitment was made. Tables for the Federal Reformatory for Women, Alderson, West…

  13. 40 CFR 62.13 - Federal plans.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 9 2012-07-01 2012-07-01 false Federal plans. 62.13 Section 62.13... PROMULGATION OF STATE PLANS FOR DESIGNATED FACILITIES AND POLLUTANTS General Provisions § 62.13 Federal plans. The Federal plans apply to owners and operators of affected facilities that are not covered by an...

  14. Study of federal microwave standards

    SciTech Connect

    David, L.

    1980-08-01

    Present and future federal regulatory processes which may impact the permissible levels of microwave radiation emitted by the SPS Microwave Power Transmission (MPTS) were studied. An historical development of US occupational and public microwave standards includes an overview of Western and East European philosophies of environmental protection and neurophysiology which have led to the current widely differing maximum permissible exposure limits to microwaves. The possible convergence of microwave standards is characterized by a lowering of Western exposure levels while Eastern countries consider standard relaxation. A trend toward stricter controls on activities perceived as harmful to public health is under way as is interest in improving the federal regulatory process. Particularly relevant to SPS is the initiation of long-term, low-level microwave exposure programs. Coupled with new developments in instrumentation and dosimetry, the results from chronic exposure program and population exposure studies could be expected within the next five to ten years. Also discussed is the increasing public concern that rf energy is yet another hazardous environmental agent.

  15. Leasing of federal geothermal resources

    NASA Technical Reports Server (NTRS)

    Stone, R. T.

    1974-01-01

    Pursuant to the Geothermal Steam Act of 1970 and the regulations published on December 21, 1973, the first Federal geothermal competitive lease sale was held on January 22, 1974, by the Department of the Interior, offering 33 tracts totalling over 50,000 acres in three Known Geothermal Resource Areas in California. On January 1, 1974, Federal lands outside Known Geothermal Resource Areas were opened to noncompetitive lease applications, of which, 3,763 had been received by June 1, 1974. During fiscal year 1974, a total of 22 competitive leases had been issued in California and Oregon. The principal components in the Department involved in the leasing program are the Geological Survey and the Bureau of Land Management. The former has jurisdiction over drilling and production operations and other activities in the immediate area of operations. The latter receives applications and issues leases and is responsible for managing leased lands under its jurisdiction outside the area of operations. The interrelationships of the above agencies and the procedures in the leasing program are discussed.

  16. Role of Misfolded N-CoR Mediated Transcriptional Deregulation of Flt3 in Acute Monocytic Leukemia (AML)-M5 Subtype

    PubMed Central

    Nin, Dawn Sijin; Kok, Wai Kay; Li, Feng; Takahashi, Shinichiro; Chng, Wee Joo; Khan, Matiullah

    2012-01-01

    The nuclear receptor co-repressor (N-CoR) is a key component of the generic multi-protein complex involved in transcriptional control. Flt3, a key regulator of hematopoietic cell growth, is frequently deregulated in AML (acute myeloid leukemia). Here, we report that loss of N-CoR-mediated transcriptional control of Flt3 due to misfolding, contributes to malignant growth in AML of the M5 subtype (AML-M5). An analysis of hematopoietic genes in AML cells led to the identification of Flt3 as a transcriptional target of N-CoR. Flt3 level was inversely related to N-CoR status in various leukemia cells. N-CoR was associated with the Flt3 promoter in-vivo, and a reporter driven by the Flt3 promoter was effectively repressed by N-CoR. Blocking N-CoR loss with Genistein; an inhibitor of N-CoR misfolding, significantly down-regulated Flt3 levels regardless of the Flt3 receptor mutational status and promoted the differentiation of AML-M5 cells. While stimulation of the Flt3 receptor with the Flt3 ligand triggered N-CoR loss, Flt3 antibody mediated blockade of Flt3 ligand-receptor binding led to N-CoR stabilization. Genetic ablation of N-CoR potentiated Flt3 ligand induced proliferation of BA/F3 cells. These findings suggest that N-CoR-induced repression of Flt3 might be crucial for limiting the contribution of the Flt3 signaling pathway on the growth potential of leukemic cells and its deregulation due to N-CoR loss in AML-M5, could contribute to malignant growth by conferring a proliferative advantage to the leukemic blasts. Therapeutic restoration of N-CoR function could thus be a useful approach in restricting the contribution of the Flt3 signaling pathway in AML-M5 pathogenesis. PMID:22514634

  17. An optimization-based approach for facility energy management with uncertainties, and, Power portfolio optimization in deregulated electricity markets with risk management

    NASA Astrophysics Data System (ADS)

    Xu, Jun

    Topic 1. An Optimization-Based Approach for Facility Energy Management with Uncertainties. Effective energy management for facilities is becoming increasingly important in view of the rising energy costs, the government mandate on the reduction of energy consumption, and the human comfort requirements. This part of dissertation presents a daily energy management formulation and the corresponding solution methodology for HVAC systems. The problem is to minimize the energy and demand costs through the control of HVAC units while satisfying human comfort, system dynamics, load limit constraints, and other requirements. The problem is difficult in view of the fact that the system is nonlinear, time-varying, building-dependent, and uncertain; and that the direct control of a large number of HVAC components is difficult. In this work, HVAC setpoints are the control variables developed on top of a Direct Digital Control (DDC) system. A method that combines Lagrangian relaxation, neural networks, stochastic dynamic programming, and heuristics is developed to predict the system dynamics and uncontrollable load, and to optimize the setpoints. Numerical testing and prototype implementation results show that our method can effectively reduce total costs, manage uncertainties, and shed the load, is computationally efficient. Furthermore, it is significantly better than existing methods. Topic 2. Power Portfolio Optimization in Deregulated Electricity Markets with Risk Management. In a deregulated electric power system, multiple markets of different time scales exist with various power supply instruments. A load serving entity (LSE) has multiple choices from these instruments to meet its load obligations. In view of the large amount of power involved, the complex market structure, risks in such volatile markets, stringent constraints to be satisfied, and the long time horizon, a power portfolio optimization problem is of critical importance but difficulty for an LSE to serve the

  18. Deregulated E2F5/p38/SMAD3 Circuitry Reinforces the Pro-Tumorigenic Switch of TGFβ Signaling in Prostate Cancer.

    PubMed

    Majumder, Subhadipa; Bhowal, Ankur; Basu, Sanmitra; Mukherjee, Pritha; Chatterji, Urmi; Sengupta, Sanghamitra

    2016-11-01

    Transforming growth factor-β signaling exerts divergent effects on normal and cancer cells, although mechanism underlying this differential behavior remains unclear. In this study, expression of 94 genes pertaining to the TGF-β signaling pathway was compared between tumor and benign tissue samples from the human prostate gland to identify major discriminators driving prostate carcinogenesis. E2F5 was identified as one of the most deregulated genes in prostate cancer tissues, predominantly in samples with Gleason-score 6. Expression of other deregulated components of TGF-β signaling was examined by qRT-PCR, Western blot, and immune-staining. Function of E2F5 and p38 in prostate cancer was investigated using siRNA-treatment of PC3 cell-line followed by analyses of associated components and cell cycle. Observations revealed that E2F5 overexpression was accompanied by significantly higher phosphorylation of SMAD3 at Ser-208 in the linker region (pSMAD3L) and p38 in tumor tissue. A striking difference in SMAD3 phosphorylation, marked by preponderance of pSMAD3L and pSMAD3C (Ser-423 and 425) in tumor and benign tissues, respectively was noted. Co-localization of E2F5 with pSMAD3L in the nuclei of tumor and PC3 cells indicated a functional interface between the proteins. Downregulation of E2F5 and p38 in PC3 cells resulted in marked reduction of phosphorylation of SMAD3 and perturbation of cell cycle with an arrest of cells in G1 . Our findings unearthed that E2F5/p38 axis played a cardinal role in uncontrolled cellular proliferation in prostate cancer through pSMAD3L activation. It also underscores a strong potential for E2F5 to be incorporated as a tool in early detection of prostate cancer. J. Cell. Physiol. 231: 2482-2492, 2016. © 2016 Wiley Periodicals, Inc. PMID:26919443

  19. Federal ten-year buildings plan

    SciTech Connect

    Not Available

    1983-09-01

    This federal 10-year buildings plan is required by Section 381 of the Energy Policy and Conservation Act (EPCA), as amended, which requires the President to the extent of his authority under other law, to implement a 10-year plan for energy conservation in federal buildings. This document, the federal 10-year buildings plan, states the goals and objectives of the Federal Buildings Program. It describes the characteristics of the federal building inventory, a strategy for achieving program goals, the responsibilities of participants, planning guidance, implementation activities, and provides a program status summary.

  20. Promoting cooperative federalism through state shared savings.

    PubMed

    Weil, Alan

    2013-08-01

    The Affordable Care Act is transforming American federalism and creating strain between the states and the federal government. By expanding the scale of intergovernmental health programs, creating new state requirements, and setting the stage for increased federal fiscal oversight, the act has disturbed an uneasy truce in American federalism. This article outlines a policy proposal designed to harness cooperative federalism, based on the shared state and federal desire to control health care cost growth. The proposal, which borrows features of the Medicare Shared Savings Program, would provide states with an incentive in the form of an increased share of the savings they generate in programs that have federal financial participation, as long as they meet defined performance standards.

  1. Promoting cooperative federalism through state shared savings.

    PubMed

    Weil, Alan

    2013-08-01

    The Affordable Care Act is transforming American federalism and creating strain between the states and the federal government. By expanding the scale of intergovernmental health programs, creating new state requirements, and setting the stage for increased federal fiscal oversight, the act has disturbed an uneasy truce in American federalism. This article outlines a policy proposal designed to harness cooperative federalism, based on the shared state and federal desire to control health care cost growth. The proposal, which borrows features of the Medicare Shared Savings Program, would provide states with an incentive in the form of an increased share of the savings they generate in programs that have federal financial participation, as long as they meet defined performance standards. PMID:23884699

  2. 77 FR 48970 - Notice of Proposed Information Collection Requests; Federal Student Aid; 2013-2014 Federal...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-15

    ... Notice of Proposed Information Collection Requests; Federal Student Aid; 2013-2014 Federal Student Aid... individuals applying for federal student aid including the Free Application for Federal Student Aid (FAFSA) and the Student Aid Report (SAR). DATES: Interested persons are invited to submit comments on...

  3. 34 CFR 682.501 - Extent of Federal guarantee under the Federal GSL programs.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... LOAN (FFEL) PROGRAM Federal Guaranteed Student Loan Programs § 682.501 Extent of Federal guarantee... Secretary's guarantee liability on any Federal GSL loan is 100 percent of the unpaid principal balance and... of the amount of the Federal GSL loans in repayment at the end of the preceding fiscal year,...

  4. 34 CFR 682.501 - Extent of Federal guarantee under the Federal GSL programs.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... LOAN (FFEL) PROGRAM Federal Guaranteed Student Loan Programs § 682.501 Extent of Federal guarantee... Secretary's guarantee liability on any Federal GSL loan is 100 percent of the unpaid principal balance and... of the amount of the Federal GSL loans in repayment at the end of the preceding fiscal year,...

  5. 34 CFR 682.501 - Extent of Federal guarantee under the Federal GSL programs.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... LOAN (FFEL) PROGRAM Federal Guaranteed Student Loan Programs § 682.501 Extent of Federal guarantee... Secretary's guarantee liability on any Federal GSL loan is 100 percent of the unpaid principal balance and... of the amount of the Federal GSL loans in repayment at the end of the preceding fiscal year,...

  6. 75 FR 19167 - Federal Acquisition Regulation; Federal Acquisition Circular 2005-41; Introduction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-13

    ..., Use of Project Labor Agreements for Federal Construction Projects; Federal Acquisition Circular 2005... Project Labor Agreements for Federal Construction Projects 2009-005 Woodson. SUPPLEMENTARY INFORMATION: A... for Federal Construction Projects (FAR Case 2009-005) This final rule amends the FAR to...

  7. Federal Environmental Reporting Requirements Handbook

    SciTech Connect

    1990-05-01

    The Environmental Reporting Requirements Handbook has been developed by DOE Headquarters' Environmental Guidance Division (EH-231) in order to assist DOE Field Organizations in the identification of the various reporting the notification requirements mandated by Federal environmental laws, regulations, and Executive Orders. The Handbook makes a distinction between ''routine'' and ''non-routine'' reporting/notification requirements. Routine reporting requirements include the submission of documents that are required either on a regular basis, such as annual or biennial reports, or periodic notifications that result from what would be considered ''normal'' operations, such as Material Safety Data Sheet (MSDS) updates that are required when new information not contained on previous MSDS submissions is discovered. Non-routine reporting requirements are generally associated with occurrences that represent significant deviations from regulated or planned performance; examples include the unintentional discharge of oil or hazardous substances.

  8. UV Light Potentiates STING (Stimulator of Interferon Genes)-dependent Innate Immune Signaling through Deregulation of ULK1 (Unc51-like Kinase 1).

    PubMed

    Kemp, Michael G; Lindsey-Boltz, Laura A; Sancar, Aziz

    2015-05-01

    The mechanism by which ultraviolet (UV) wavelengths of sunlight trigger or exacerbate the symptoms of the autoimmune disorder lupus erythematosus is not known but may involve a role for the innate immune system. Here we show that UV radiation potentiates STING (stimulator of interferon genes)-dependent activation of the immune signaling transcription factor interferon regulatory factor 3 (IRF3) in response to cytosolic DNA and cyclic dinucleotides in keratinocytes and other human cells. Furthermore, we find that modulation of this innate immune response also occurs with UV-mimetic chemical carcinogens and in a manner that is independent of DNA repair and several DNA damage and cell stress response signaling pathways. Rather, we find that the stimulation of STING-dependent IRF3 activation by UV is due to apoptotic signaling-dependent disruption of ULK1 (Unc51-like kinase 1), a pro-autophagic protein that negatively regulates STING. Thus, deregulation of ULK1 signaling by UV-induced DNA damage may contribute to the negative effects of sunlight UV exposure in patients with autoimmune disorders.

  9. Identification of deregulation of apoptosis and cell cycle in neuroendocrine tumors of the lung via NanoString nCounter expression analysis

    PubMed Central

    Walter, Robert Fred Henry; Werner, Robert; Ting, Saskia; Vollbrecht, Claudia; Theegarten, Dirk; Christoph, Daniel Christian; Schmid, Kurt Werner; Wohlschlaeger, Jeremias; Mairinger, Fabian Dominik

    2015-01-01

    Background Neuroendocrine tumors of the lung comprise typical (TC) and atypical carcinoids (AC), large-cell neuroendocrine cancer (LCNEC) and small-cell lung cancer (SCLC). Cell cycle and apoptosis are key pathways of multicellular homeostasis and deregulation of these pathways is associated with cancerogenesis. Materials and Methods Sixty representative FFPE-specimens (16 TC, 13 AC, 16 LCNEC and 15 SCLC) were used for mRNA expression analysis using the NanoString technique. Eight genes related to apoptosis and ten genes regulating key points of cell cycle were investigated. Results ASCL1, BCL2, CASP8, CCNE1, CDK1, CDK2, CDKN1A and CDKN2A showed lower expression in carcinoids compared to carcinomas. In contrast, CCNE1 and CDK6 showed elevated expression in carcinoids compared to carcinomas. The calculated BCL2/BAX ratio showed increasing values from TC to SCLC. Between SCLC and LCNEC CDK2, CDKN1B, CDKN2A and PNN expression was significantly different with higher expression in SCLC. Conclusion Carcinoids have increased CDK4/6 and CCND1 expression controlling RB1 phosphorylation via this signaling cascade. CDK2 and CCNE1 were increased in carcinomas showing that these use the opposite way to control RB1. BAX and BCL2 are antagonists in regulating apoptosis. BCL2 expression increased over BAX expression with increasing malignancy of the tumor from TC to SCLC. PMID:26008974

  10. A Probabilistic Boolean Network Approach for the Analysis of Cancer-Specific Signalling: A Case Study of Deregulated PDGF Signalling in GIST

    PubMed Central

    Wiesinger, Monique; Bahlawane, Christelle; Haan, Serge; Sauter, Thomas

    2016-01-01

    Background Signal transduction networks are increasingly studied with mathematical modelling approaches while each of them is suited for a particular problem. For the contextualisation and analysis of signalling networks with steady-state protein data, we identified probabilistic Boolean network (PBN) as a promising framework which could capture quantitative changes of molecular changes at steady-state with a minimal parameterisation. Results and Conclusion In our case study, we successfully applied the PBN approach to model and analyse the deregulated Platelet-Derived Growth Factor (PDGF) signalling pathway in Gastrointestinal Stromal Tumour (GIST). We experimentally determined a rich and accurate dataset of steady-state profiles of selected downstream kinases of PDGF-receptor-alpha mutants in combination with inhibitor treatments. Applying the tool optPBN, we fitted a literature-derived candidate network model to the training dataset consisting of single perturbation conditions. Model analysis suggested several important crosstalk interactions. The validity of these predictions was further investigated experimentally pointing to relevant ongoing crosstalk from PI3K to MAPK signalling in tumour cells. The refined model was evaluated with a validation dataset comprising multiple perturbation conditions. The model thereby showed excellent performance allowing to quantitatively predict the combinatorial responses from the individual treatment results in this cancer setting. The established optPBN pipeline is also widely applicable to gain a better understanding of other signalling networks at steady-state in a context-specific fashion. PMID:27232499

  11. Deregulation of DNMT1, DNMT3B and miR-29s in Burkitt lymphoma suggests novel contribution for disease pathogenesis.

    PubMed

    Robaina, Marcela C; Mazzoccoli, Luciano; Arruda, Viviane Oliveira; Reis, Flaviana Ruade de Souza; Apa, Alexandre Gustavo; de Rezende, Lidia Maria Magalhães; Klumb, Claudete Esteves

    2015-04-01

    Methylation of CpG islands in promoter gene regions is frequently observed in lymphomas. DNA methylation is established by DNA methyltransferases (DNMTs). DNMT1 maintains methylation patterns, while DNMT3A and DNMT3B are critical for de novo DNA methylation. Little is known about the expression of DNMTs in lymphomas. DNMT3A and 3B genes can be regulated post-transcriptionally by miR-29 family. Here, we demonstrated for the first time the overexpression of DNMT1 and DNMT3B in Burkitt lymphoma (BL) tumor samples (69% and 86%, respectively). Specifically, the treatment of two BL cell lines with the DNMT inhibitor 5-aza-dC decreased DNMT1 and DNMT3B protein levels and inhibited cell growth. Additionally, miR-29a, miR-29b and miR-29c levels were significantly decreased in the BL tumor samples. Besides, the ectopic expression of miR-29a, miR-29b and miR-29c reduced the DNMT3B expression and miR-29a and miR-29b lead to increase of p16(INK4a) mRNA expression. Altogether, our data suggest that deregulation of DNMT1, DNMT3B and miR29 may be involved in BL pathogenesis. PMID:25746661

  12. Transcriptomics: A Step behind the Comprehension of the Polygenic Influence on Oxidative Stress, Immune Deregulation, and Mitochondrial Dysfunction in Chronic Kidney Disease

    PubMed Central

    2016-01-01

    Chronic kidney disease (CKD) is an increasing and global health problem with a great economic burden for healthcare system. Therefore to slow down the progression of this condition is a main objective in nephrology. It has been extensively reported that microinflammation, immune system deregulation, and oxidative stress contribute to CKD progression. Additionally, dialysis worsens this clinical condition because of the contact of blood with bioincompatible dialytic devices. Numerous studies have shown the close link between immune system impairment and CKD but most have been performed using classical biomolecular strategies. These methodologies are limited in their ability to discover new elements and enable measuring the simultaneous influence of multiple factors. The “omics” techniques could overcome these gaps. For example, transcriptomics has revealed that mitochondria and inflammasome have a role in pathogenesis of CKD and are pivotal elements in the cellular alterations leading to systemic complications. We believe that a larger employment of this technique, together with other “omics” methodologies, could help clinicians to obtain new pathogenetic insights, novel diagnostic biomarkers, and therapeutic targets. Finally, transcriptomics could allow clinicians to personalize therapeutic strategies according to individual genetic background (nutrigenomic and pharmacogenomic). In this review, we analyzed the available transcriptomic studies involving CKD patients. PMID:27419142

  13. Lack of glucocorticoid-induced leucine zipper (GILZ) deregulates B-cell survival and results in B-cell lymphocytosis in mice

    PubMed Central

    Bruscoli, Stefano; Biagioli, Michele; Sorcini, Daniele; Frammartino, Tiziana; Cimino, Monica; Sportoletti, Paolo; Mazzon, Emanuela; Bereshchenko, Oxana

    2015-01-01

    Glucocorticoids (GC) are widely used as antiinflammatory/immunosuppressive drugs and antitumor agents in several types of lymphoma and leukemia. Therapeutic doses of GC induce growth-suppressive and cytotoxic effects on various leukocytes including B cells. Molecular mechanisms of GC action include induction of GC target genes. Glucocorticoid-induced leucine zipper (GILZ) is a rapidly, potently, and invariably GC-induced gene. It mediates a number of GC effects, such as control of cell proliferation, differentiation, and apoptosis. Here we show that deletion of GILZ in mice leads to an accumulation of B lymphocytes in the bone marrow, blood, and lymphoid tissues. Gilz knockout (KO) mice develop a progressive nonlethal B lymphocytosis, with expansion of B220+ cells in the bone marrow and in the periphery, dependent on increased B-cell survival. Decreased B-cell apoptosis in mice lacking GILZ correlates with increased NF-κB transcriptional activity and Bcl-2 expression. B cell–specific gilz KO mice confirmed that the effect of GILZ deletion is B-cell self-intrinsic. These results establish GILZ as an important regulator of B-cell survival and suggest that the deregulation of GILZ expression could be implicated in the pathogenesis of B-cell disorders. PMID:26276664

  14. UV Light Potentiates STING (Stimulator of Interferon Genes)-dependent Innate Immune Signaling through Deregulation of ULK1 (Unc51-like Kinase 1)*

    PubMed Central

    Kemp, Michael G.; Lindsey-Boltz, Laura A.; Sancar, Aziz

    2015-01-01

    The mechanism by which ultraviolet (UV) wavelengths of sunlight trigger or exacerbate the symptoms of the autoimmune disorder lupus erythematosus is not known but may involve a role for the innate immune system. Here we show that UV radiation potentiates STING (stimulator of interferon genes)-dependent activation of the immune signaling transcription factor interferon regulatory factor 3 (IRF3) in response to cytosolic DNA and cyclic dinucleotides in keratinocytes and other human cells. Furthermore, we find that modulation of this innate immune response also occurs with UV-mimetic chemical carcinogens and in a manner that is independent of DNA repair and several DNA damage and cell stress response signaling pathways. Rather, we find that the stimulation of STING-dependent IRF3 activation by UV is due to apoptotic signaling-dependent disruption of ULK1 (Unc51-like kinase 1), a pro-autophagic protein that negatively regulates STING. Thus, deregulation of ULK1 signaling by UV-induced DNA damage may contribute to the negative effects of sunlight UV exposure in patients with autoimmune disorders. PMID:25792739

  15. UV Light Potentiates STING (Stimulator of Interferon Genes)-dependent Innate Immune Signaling through Deregulation of ULK1 (Unc51-like Kinase 1).

    PubMed

    Kemp, Michael G; Lindsey-Boltz, Laura A; Sancar, Aziz

    2015-05-01

    The mechanism by which ultraviolet (UV) wavelengths of sunlight trigger or exacerbate the symptoms of the autoimmune disorder lupus erythematosus is not known but may involve a role for the innate immune system. Here we show that UV radiation potentiates STING (stimulator of interferon genes)-dependent activation of the immune signaling transcription factor interferon regulatory factor 3 (IRF3) in response to cytosolic DNA and cyclic dinucleotides in keratinocytes and other human cells. Furthermore, we find that modulation of this innate immune response also occurs with UV-mimetic chemical carcinogens and in a manner that is independent of DNA repair and several DNA damage and cell stress response signaling pathways. Rather, we find that the stimulation of STING-dependent IRF3 activation by UV is due to apoptotic signaling-dependent disruption of ULK1 (Unc51-like kinase 1), a pro-autophagic protein that negatively regulates STING. Thus, deregulation of ULK1 signaling by UV-induced DNA damage may contribute to the negative effects of sunlight UV exposure in patients with autoimmune disorders. PMID:25792739

  16. Deregulation of XBP1 expression contributes to myocardial vascular endothelial growth factor-A expression and angiogenesis during cardiac hypertrophy in vivo.

    PubMed

    Duan, Quanlu; Ni, Li; Wang, Peihua; Chen, Chen; Yang, Lei; Ma, Ben; Gong, Wei; Cai, Zhejun; Zou, Ming-Hui; Wang, Dao Wen

    2016-08-01

    Endoplasmic reticulum (ER) stress has been reported to be involved in many cardiovascular diseases such as atherosclerosis, diabetes, myocardial ischemia, and hypertension that ultimately result in heart failure. XBP1 is a key ER stress signal transducer and an important pro-survival factor of the unfolded protein response (UPR) in mammalian cells. The aim of this study was to establish a role for XBP1 in the deregulation of pro-angiogenic factor VEGF expression and potential regulatory mechanisms in hypertrophic and failing heart. Western blots showed that myocardial XBP1s protein was significantly increased in both isoproterenol (ISO)-induced and pressure-overload-induced hypertrophic and failing heart compared to normal control. Furthermore, XBP1 silencing exacerbates ISO-induced cardiac dysfunction along with a reduction of myocardial capillary density and cardiac expression of pro-angiogenic factor VEGF-A in vivo. Consistently, experiments in cultured cardiomyocytes H9c2 (2-1) cells showed that UPR-induced VEGF-A upregulation was determined by XBP1 expression level. Importantly, VEGF-A expression was increased in failing human heart tissue and blood samples and was correlated with the levels of XBP1. These results suggest that XBP1 regulates VEGF-mediated cardiac angiogenesis, which contributes to the progression of adaptive hypertrophy, and might provide novel targets for prevention and treatment of heart failure. PMID:27133203

  17. Deregulation of Fragile X-related protein 1 by the lipodystrophic lamin A p.R482W mutation elicits a myogenic gene expression program in preadipocytes.

    PubMed

    Oldenburg, Anja R; Delbarre, Erwan; Thiede, Bernd; Vigouroux, Corinne; Collas, Philippe

    2014-03-01

    The nuclear lamina is implicated in the regulation of various nuclear functions. Several laminopathy-causing mutations in the LMNA gene, notably the p.R482W substitution linked to familial partial lipodystrophy type 2 (FPLD2), are clustered in the immunoglobulin fold of lamin A. We report a functional association between lamin A and fragile X-related protein 1 (FXR1P), a protein of the fragile X-related family involved in fragile X syndrome. Searching for proteins differentially interacting with the immunoglobulin fold of wild-type and R482W mutant lamin A, we identify FXR1P as a novel component of the lamin A protein network. The p.R482W mutation abrogates interaction of FXR1P with lamin A. Fibroblasts from FPLD2 patients display elevated levels of FXR1P and delocalized FXR1P. In human adipocyte progenitors, deregulation of lamin A expression leads to FXR1P up-regulation, impairment of adipogenic differentiation and induction of myogenin expression. FXR1P overexpression also stimulates a myogenic gene expression program in these cells. Our results demonstrate a cross-talk between proteins hitherto implicated in two distinct mesodermal pathologies. We propose a model where the FPLD2 lamin A p.R482W mutation elicits, through up-regulation of FXR1P, a remodeling of an adipogenic differentiation program into a myogenic program.

  18. A deregulated expression of estrogen-target genes is associated with an altered response to estradiol in aged rats perinatally exposed to bisphenol A.

    PubMed

    Vigezzi, Lucía; Ramos, Jorge G; Kass, Laura; Tschopp, María V; Muñoz-de-Toro, Mónica; Luque, Enrique H; Bosquiazzo, Verónica L

    2016-05-01

    Here we assessed the effects of perinatal exposure to bisphenol A (BPA) on the uterine response to 17β-estradiol (E2) in aged rats. Pregnant rats were orally exposed to 0.5 or 50 μg BPA/kg/day from gestational day 9 until weaning. On postnatal day (PND) 360, the rats were ovariectomized and treated with E2 for three months. The uterine tissue of BPA50 and BPA0.5 rats showed increased density of glands with squamous metaplasia (GSM) and glands with daughter glands respectively. Wnt7a expression was lower in GSM of BPA50 rats than in controls. The expression of estrogen receptor 1 (ESR1) and its 5'- untranslated exons ESR1-O and ESR1-OT was lower in BPA50 rats. Both doses of BPA modified the expression of coactivator proteins and epigenetic regulatory enzymes. Thus, perinatal BPA-exposed rats showed different glandular abnormalities associated with deregulated expression of E2-target genes. Different mechanisms would be involved depending on the BPA dose administered. PMID:26898831

  19. A deregulated expression of estrogen-target genes is associated with an altered response to estradiol in aged rats perinatally exposed to bisphenol A.

    PubMed

    Vigezzi, Lucía; Ramos, Jorge G; Kass, Laura; Tschopp, María V; Muñoz-de-Toro, Mónica; Luque, Enrique H; Bosquiazzo, Verónica L

    2016-05-01

    Here we assessed the effects of perinatal exposure to bisphenol A (BPA) on the uterine response to 17β-estradiol (E2) in aged rats. Pregnant rats were orally exposed to 0.5 or 50 μg BPA/kg/day from gestational day 9 until weaning. On postnatal day (PND) 360, the rats were ovariectomized and treated with E2 for three months. The uterine tissue of BPA50 and BPA0.5 rats showed increased density of glands with squamous metaplasia (GSM) and glands with daughter glands respectively. Wnt7a expression was lower in GSM of BPA50 rats than in controls. The expression of estrogen receptor 1 (ESR1) and its 5'- untranslated exons ESR1-O and ESR1-OT was lower in BPA50 rats. Both doses of BPA modified the expression of coactivator proteins and epigenetic regulatory enzymes. Thus, perinatal BPA-exposed rats showed different glandular abnormalities associated with deregulated expression of E2-target genes. Different mechanisms would be involved depending on the BPA dose administered.

  20. The Domino Effects of Federal Research Funding

    PubMed Central

    Graddy-Reed, Alexandra; Feldman, Maryann P.

    2016-01-01

    The extent to which federal investment in research crowds out or decreases incentives for investment from other funding sources remains an open question. Scholarship on research funding has focused on the relationship between federal and industry or, more comprehensively, non-federal funding without disentangling the other sources of research support that include nonprofit organizations and state and local governments. This paper extends our understanding of academic research support by considering the relationships between federal and non-federal funding sources provided by the National Science Foundation Higher Education Research and Development Survey. We examine whether federal research investment serves as a complement or substitute for state and local government, nonprofit, and industry research investment using the population of research-active academic science fields at U.S. doctoral granting institutions. We use a system of two equations that instruments with prior levels of both federal and non-federal funding sources and accounts for time-invariant academic institution-field effects through first differencing. We estimate that a 1% increase in federal research funding is associated with a 0.411% increase in nonprofit research funding, a 0.217% increase in state and local research funding, and a 0.468% increase in industry research funding, respectively. Results indicate that federal funding plays a fundamental role in inducing complementary investments from other funding sources, with impacts varying across academic division, research capacity, and institutional control. PMID:27327509